Publications by authors named "Rodrigo V Honorato"

15 Publications

  • Page 1 of 1

Information-driven modeling of biomolecular complexes.

Curr Opin Struct Biol 2021 Jun 14;70:70-77. Epub 2021 Jun 14.

Bijvoet Centre for Biomolecular Research, Faculty of Science, Department of Chemistry, Utrecht University, Padualaan 8, Utrecht, 3584CH, Netherlands. Electronic address:

Proteins play crucial roles in every cellular process by interacting with each other, nucleic acids, metabolites, and other molecules. The resulting assemblies can be very large and intricate and pose challenges to experimental methods. In the current era of integrative modeling, it is often only by a combination of various experimental techniques and computations that three-dimensional models of those molecular machines can be obtained. Among the various computational approaches available, molecular docking is often the method of choice when it comes to predicting three-dimensional structures of complexes. Docking can generate particularly accurate models when taking into account the available information on the complex of interest. We review here the use of experimental and bioinformatics data in protein-protein docking, describing recent software developments and highlighting applications for the modeling of antibody-antigen complexes and membrane protein complexes, and the use of evolutionary and shape information.
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http://dx.doi.org/10.1016/j.sbi.2021.05.003DOI Listing
June 2021

An overview of data-driven HADDOCK strategies in CAPRI rounds 38-45.

Proteins 2020 08 7;88(8):1029-1036. Epub 2020 Jan 7.

Faculty of Science, Department of Chemistry, Bijvoet Center for Biomolecular Research, Computational Structural Biology Group, Utrecht University, Utrecht, The Netherlands.

Our information-driven docking approach HADDOCK has demonstrated a sustained performance since the start of its participation to CAPRI. This is due, in part, to its ability to integrate data into the modeling process, and to the robustness of its scoring function. We participated in CAPRI both as server and manual predictors. In CAPRI rounds 38-45, we have used various strategies depending on the available information. These ranged from imposing restraints to a few residues identified from literature as being important for the interaction, to binding pockets identified from homologous complexes or template-based refinement/CA-CA restraint-guided docking from identified templates. When relevant, symmetry restraints were used to limit the conformational sampling. We also tested for a large decamer target a new implementation of the MARTINI coarse-grained force field in HADDOCK. Overall, we obtained acceptable or better predictions for 13 and 11 server and manual submissions, respectively, out of the 22 interfaces. Our server performance (acceptable or higher-quality models when considering the top 10) was better (59%) than the manual (50%) one, in which we typically experiment with various combinations of protocols and data sources. Again, our simple scoring function based on a linear combination of intermolecular van der Waals and electrostatic energies and an empirical desolvation term demonstrated a good performance in the scoring experiment with a 63% success rate across all 22 interfaces. An analysis of model quality indicates that, while we are consistently performing well in generating acceptable models, there is room for improvement for generating/identifying higher quality models.
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http://dx.doi.org/10.1002/prot.25869DOI Listing
August 2020

MARTINI-Based Protein-DNA Coarse-Grained HADDOCKing.

Front Mol Biosci 2019 1;6:102. Epub 2019 Oct 1.

Faculty of Science-Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, Netherlands.

Modeling biomolecular assemblies is an important field in computational structural biology. The inherent complexity of their energy landscape and the computational cost associated with modeling large and complex assemblies are major drawbacks for integrative modeling approaches. The so-called coarse-graining approaches, which reduce the degrees of freedom of the system by grouping several atoms into larger "pseudo-atoms," have been shown to alleviate some of those limitations, facilitating the identification of the global energy minima assumed to correspond to the native state of the complex, while making the calculations more efficient. Here, we describe and assess the implementation of the MARTINI force field for DNA into HADDOCK, our integrative modeling platform. We combine it with our previous implementation for protein-protein coarse-grained docking, enabling coarse-grained modeling of protein-nucleic acid complexes. The system is modeled using MARTINI topologies and interaction parameters during the rigid body docking and semi-flexible refinement stages of HADDOCK, and the resulting models are then converted back to atomistic resolution by an atom-to-bead distance restraints-guided protocol. We first demonstrate the performance of this protocol using 44 complexes from the protein-DNA docking benchmark, which shows an overall ~6-fold speed increase and maintains similar accuracy as compared to standard atomistic calculations. As a proof of concept, we then model the interaction between the PRC1 and the nucleosome (a former CAPRI target in round 31), using the same information available at the time the target was offered, and compare all-atom and coarse-grained models.
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http://dx.doi.org/10.3389/fmolb.2019.00102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779769PMC
October 2019

Blind prediction of homo- and hetero-protein complexes: The CASP13-CAPRI experiment.

Proteins 2019 12 25;87(12):1200-1221. Epub 2019 Oct 25.

School of Physics, Huazhong University of Science and Technology, Wuhan, Hubei, China.

We present the results for CAPRI Round 46, the third joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo-oligomers and 6 heterocomplexes. Eight of the homo-oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher-order assemblies. These were more difficult to model, as their prediction mainly involved "ab-initio" docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance "gap" was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template-based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements.
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http://dx.doi.org/10.1002/prot.25838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274794PMC
December 2019

Less Is More: Coarse-Grained Integrative Modeling of Large Biomolecular Assemblies with HADDOCK.

J Chem Theory Comput 2019 Nov 10;15(11):6358-6367. Epub 2019 Oct 10.

Bijvoet Center for Biomolecular Research, Faculty of Science - Chemistry , Utrecht University , Utrecht 3584CH , The Netherlands.

Predicting the 3D structure of protein interactions remains a challenge in the field of computational structural biology. This is in part due to difficulties in sampling the complex energy landscape of multiple interacting flexible polypeptide chains. Coarse-graining approaches, which reduce the number of degrees of freedom of the system, help address this limitation by smoothing the energy landscape, allowing an easier identification of the global energy minimum. They also accelerate the calculations, allowing for modeling larger assemblies. Here, we present the implementation of the MARTINI coarse-grained force field for proteins into HADDOCK, our integrative modeling platform. Docking and refinement are performed at the coarse-grained level, and the resulting models are then converted back to atomistic resolution through a distance restraints-guided morphing procedure. Our protocol, tested on the largest complexes of the protein docking benchmark 5, shows an overall ∼7-fold speed increase compared to standard all-atom calculations, while maintaining a similar accuracy and yielding substantially more near-native solutions. To showcase the potential of our method, we performed simultaneous 7 body docking to model the 1:6 KaiC-KaiB complex, integrating mutagenesis and hydrogen/deuterium exchange data from mass spectrometry with symmetry restraints, and validated the resulting models against a recently published cryo-EM structure.
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http://dx.doi.org/10.1021/acs.jctc.9b00310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854652PMC
November 2019

Thioredoxin-1 Negatively Modulates ADAM17 Activity Through Direct Binding and Indirect Reductive Activity.

Antioxid Redox Signal 2018 09 27;29(8):717-734. Epub 2018 Feb 27.

1 Laboratório Nacional de Biociências , LNBio, CNPEM, Campinas, Brazil .

Aims: A disintegrin and metalloprotease 17 (ADAM17) modulates signaling events by releasing surface protein ectodomains such as TNFa and the EGFR-ligands. We have previously characterized cytoplasmic thioredoxin-1 (Trx-1) as a partner of ADAM17 cytoplasmic domain. Still, the mechanism of ADAM17 regulation by Trx-1 is unknown, and it has become of paramount importance to assess the degree of influence that Trx-1 has on metalloproteinase ADAM17.

Results: Combining discovery and targeted proteomic approaches, we uncovered that Trx-1 negatively regulates ADAM17 by direct and indirect effect. We performed cell-based assays with synthetic peptides and site-directed mutagenesis, and we demonstrated that the interaction interface of Trx-1 and ADAM17 is important for the negative regulation of ADAM17 activity. However, both Trx-1 and catalytic site mutant Trx-1 rescued ADAM17 activity, although the interaction with Trx-1 was unaffected, suggesting an indirect effect of Trx-1. We confirmed that the Trx-1 mutant showed diminished reductive capacity, explaining this indirect effect on increasing ADAM17 activity through oxidant levels. Interestingly, Trx-1 mutant showed similar oxidant levels to Trx-1, even though its catalytic site was preserved. We further demonstrated that the general reactive oxygen species inhibitor, Nacetylcysteine (NAC), maintained the regulation of ADAM17 dependent of Trx-1 reductase activity levels; whereas the electron transport chain modulator, rotenone, abolished Trx-1 effect on ADAM17 activity.

Innovation: We show for the first time that the mechanism of ADAM17 regulation, Trx-1 dependent, can be by direct interaction and indirect effect, bringing new insights into the cross-talk between isomerases and mammalian metalloproteinases.

Conclusion: This unexpected Trx-1 behavior was due to more dimer formation and, consequently, the reduction of its Trx-1 reductase activity, evaluated through dimer verification, by gel filtration and mass spectrometry analysis. Antioxid. Redox Signal. 29, 717-734.
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http://dx.doi.org/10.1089/ars.2017.7297DOI Listing
September 2018

Calcium and magnesium ions modulate the oligomeric state and function of mitochondrial 2-Cys peroxiredoxins in parasites.

J Biol Chem 2017 04 14;292(17):7023-7039. Epub 2017 Mar 14.

From the Biosciences National Laboratory, National Center for Research in Energy and Materials, Rua Giuseppe Maximo Scolfaro 10000, 13083-100 Campinas/SP, Brazil,

parasites have evolved a number of strategies to cope with the harsh environmental changes during mammalian infection. One of these mechanisms involves the functional gain that allows mitochondrial 2-Cys peroxiredoxins to act as molecular chaperones when forming decamers. This function is critical for parasite infectivity in mammals, and its activation has been considered to be controlled exclusively by the enzyme redox state under physiological conditions. Herein, we have revealed that magnesium and calcium ions play a major role in modulating the ability of these enzymes to act as molecular chaperones, surpassing the redox effect. These ions are directly involved in mitochondrial metabolism and participate in a novel mechanism to stabilize the decameric form of 2-Cys peroxiredoxins in mitochondria. Moreover, we have demonstrated that a constitutively dimeric Prx1m mutant impairs the survival of under heat stress, supporting the central role of the chaperone function of Prx1m for parasites during the transition from insect to mammalian hosts.
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http://dx.doi.org/10.1074/jbc.M116.762039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409470PMC
April 2017

KVFinder: steered identification of protein cavities as a PyMOL plugin.

BMC Bioinformatics 2014 Jun 17;15:197. Epub 2014 Jun 17.

National Laboratory of Biosciences, P,O, Box 6192, CEP 13083-970 Campinas, SP, Brazil.

Background: The characterization of protein binding sites is a major challenge in computational biology. Proteins interact with a wide variety of molecules and understanding of such complex interactions is essential to gain deeper knowledge of protein function. Shape complementarity is known to be important in determining protein-ligand interactions. Furthermore, these protein structural features have been shown to be useful in assisting medicinal chemists during lead discovery and optimization.

Results: We developed KVFinder, a highly versatile and easy-to-use tool for cavity prospection and spatial characterization. KVFinder is a geometry-based method that has an innovative customization of the search space. This feature provides the possibility of cavity segmentation, which alongside with the large set of customizable parameters, allows detailed cavity analyses. Although the main focus of KVFinder is the steered prospection of cavities, we tested it against a benchmark dataset of 198 known drug targets in order to validate our software and compare it with some of the largely accepted methods. Using the one click mode, we performed better than most of the other methods, staying behind only of hybrid prospection methods. When using just one of KVFinder's customizable features, we were able to outperform all other compared methods. KVFinder is also user friendly, as it is available as a PyMOL plugin, or command-line version.

Conclusion: KVFinder presents novel usability features, granting full customizable and highly detailed cavity prospection on proteins, alongside with a friendly graphical interface. KVFinder is freely available on http://lnbio.cnpem.br/bioinformatics/main/software/.
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http://dx.doi.org/10.1186/1471-2105-15-197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071799PMC
June 2014

Mechanistic strategies for catalysis adopted by evolutionary distinct family 43 arabinanases.

J Biol Chem 2014 Mar 27;289(11):7362-73. Epub 2014 Jan 27.

From the Brazilian Biosciences National Laboratory and.

Arabinanases (ABNs, EC 3.2.1.99) are promising catalysts for environmentally friendly biomass conversion into energy and chemicals. These enzymes catalyze the hydrolysis of the α-1,5-linked L-arabinofuranoside backbone of plant cell wall arabinans releasing arabino-oligosaccharides and arabinose, the second most abundant pentose in nature. In this work, new findings about the molecular mechanisms governing activation, functional differentiation, and catalysis of GH43 ABNs are presented. Biophysical, mutational, and biochemical studies with the hyperthermostable two-domain endo-acting ABN from Thermotoga petrophila (TpABN) revealed how some GH43 ABNs are activated by calcium ions via hyperpolarization of the catalytically relevant histidine and the importance of the ancillary domain for catalysis and conformational stability. On the other hand, the two GH43 ABNs from rumen metagenome, ARN2 and ARN3, presented a calcium-independent mechanism in which sodium is the most likely substituent for calcium ions. The crystal structure of the two-domain endo-acting ARN2 showed that its ability to efficiently degrade branched substrates is due to a larger catalytic interface with higher accessibility than that observed in other ABNs with preference for linear arabinan. Moreover, crystallographic characterization of the single-domain exo-acting ARN3 indicated that its cleavage pattern producing arabinose is associated with the chemical recognition of the reducing end of the substrate imposed by steric impediments at the aglycone-binding site. By structure-guided rational design, ARN3 was converted into a classical endo enzyme, confirming the role of the extended Arg(203)-Ala(230) loop in determining its action mode. These results reveal novel molecular aspects concerning the functioning of GH43 ABNs and provide new strategies for arabinan degradation.
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http://dx.doi.org/10.1074/jbc.M113.537167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953252PMC
March 2014

P-I class metalloproteinase from Bothrops moojeni venom is a post-proline cleaving peptidase with kininogenase activity: insights into substrate selectivity and kinetic behavior.

Biochim Biophys Acta 2014 Mar 27;1844(3):545-52. Epub 2013 Dec 27.

Departamento de Biofísica, Universidade Federal de São Paulo, 04044-020 São Paulo, SP, Brazil. Electronic address:

Snake venom metalloproteinases (SVMPs) belonging to P-I class are able to hydrolyze extracellular matrix proteins and coagulation factors triggering local and systemic reactions by multiple molecular mechanisms that are not fully understood. BmooMPα-I, a P-I class SMVP from Bothrops moojeni venom, was active upon neuro- and vaso-active peptides including angiotensin I, bradykinin, neurotensin, oxytocin and substance P. Interestingly, BmooMPα-I showed a strong bias towards hydrolysis after proline residues, which is unusual for most of characterized peptidases. Moreover, the enzyme showed kininogenase activity similar to that observed in plasma and cells by kallikrein. FRET peptide assays indicated a relative promiscuity at its S2-S'2 subsites, with proline determining the scissile bond. This unusual post-proline cleaving activity was confirmed by the efficient hydrolysis of the synthetic combinatorial library MCA-GXXPXXQ-EDDnp, described as resistant for canonical peptidases, only after Pro residues. Structural analysis of the tripeptide LPL complexed with BmooMPα-I, generated by molecular dynamics simulations, assisted in defining the subsites and provided the structural basis for subsite preferences such as the restriction of basic residues at the S2 subsite due to repulsive electrostatic effects and the steric impediment for large aliphatic or aromatic side chains at the S1 subsite. These new functional and structural findings provided a further understanding of the molecular mechanisms governing the physiological effects of this important class of enzymes in envenomation process.
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http://dx.doi.org/10.1016/j.bbapap.2013.12.014DOI Listing
March 2014

Structural insights into functional overlapping and differentiation among myosin V motors.

J Biol Chem 2013 Nov 4;288(47):34131-34145. Epub 2013 Oct 4.

Brazilian Biosciences National Laboratory, National Center for Research in Energy and Materials, Campinas, São Paulo 13083-100, Brazil. Electronic address:

Myosin V (MyoV) motors have been implicated in the intracellular transport of diverse cargoes including vesicles, organelles, RNA-protein complexes, and regulatory proteins. Here, we have solved the cargo-binding domain (CBD) structures of the three human MyoV paralogs (Va, Vb, and Vc), revealing subtle structural changes that drive functional differentiation and a novel redox mechanism controlling the CBD dimerization process, which is unique for the MyoVc subclass. Moreover, the cargo- and motor-binding sites were structurally assigned, indicating the conservation of residues involved in the recognition of adaptors for peroxisome transport and providing high resolution insights into motor domain inhibition by CBD. These results contribute to understanding the structural requirements for cargo transport, autoinhibition, and regulatory mechanisms in myosin V motors.
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http://dx.doi.org/10.1074/jbc.M113.507202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837155PMC
November 2013

Structural studies of the Trypanosoma cruzi Old Yellow Enzyme: insights into enzyme dynamics and specificity.

Biophys Chem 2013 Dec 28;184:44-53. Epub 2013 Aug 28.

Laboratório Nacional de Biociências - LNBio/CNPEM-ABTLuS, Campinas, SP 13083-970, Brazil.

The flavoprotein old yellow enzyme of Trypanosoma cruzi (TcOYE) is an oxidoreductase that uses NAD(P)H as cofactor. This enzyme is clinically relevant due to its role in the action mechanism of some trypanocidal drugs used in the treatment of Chagas' disease by producing reactive oxygen species. In this work, the recombinant enzyme TcOYE was produced and collectively, X-ray crystallography, small angle X-ray scattering, analytical ultracentrifugation and molecular dynamics provided a detailed description of its structure, specificity and hydrodynamic behavior. The crystallographic structure at 1.27Å showed a classical (α/β)8 fold with the FMN prosthetic group buried at the positively-charged active-site cleft. In solution, TcOYE behaved as a globular monomer, but it exhibited a molecular envelope larger than that observed in the crystal structure, suggesting intrinsic protein flexibility. Moreover, the binding mode of β-lapachone, a trypanocidal agent, and other naphthoquinones was investigated by molecular docking and dynamics suggesting that their binding to TcOYE are stabilized mainly by interactions with the isoalloxazine ring from FMN and residues from the active-site pocket.
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http://dx.doi.org/10.1016/j.bpc.2013.08.004DOI Listing
December 2013

A specific interdomain interaction preserves the structural and binding properties of the ModA protein from the phytopathogen Xanthomonas citri domain interaction and transport in ModA.

Arch Biochem Biophys 2013 Nov 12;539(1):20-30. Epub 2013 Sep 12.

Laboratório Nacional de Biociências (LNBio), Centro de Pesquisas em Energia e Materiais (CNPEM), Campinas, SP, Brazil.

The periplasmic-binding proteins in ATP-binding cassette systems (ABC Transporters) are responsible for the capture and delivery of ligands to their specific transporters, triggering a series of ATP-driven conformational changes that leads to the transport of the ligand. Structurally consisting of two lobes, the proteins change conformation after interaction with the ligand. The structure of the molybdate-binding protein (ModA) from Xanthomonas citri, bound to molybdate, was previously solved by our group and an interdomain interaction, mediated by a salt bridge between K127 and D59, apparently supports the binding properties and keeps the domains closed. To determinate the importance of this interaction, we built two ModA mutants, K127S and D59A, and analysed their functional and structural properties. Based on a set of spectroscopic experiments, crystallisation trials, structure determination and molecular dynamics (MD) simulations, we showed that the salt bridge is essential to maintain the structure and binding properties. Additionally, the MD simulations revealed that this mutant adopted a more compact structure that packed down the ligand-binding pocket. From the closed bound to open structure, the positioning of the helices forming the dipole and the salt bridge are essential to induce an intermediate state.
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http://dx.doi.org/10.1016/j.abb.2013.09.003DOI Listing
November 2013

Identification of novel interaction between ADAM17 (a disintegrin and metalloprotease 17) and thioredoxin-1.

J Biol Chem 2012 Dec 26;287(51):43071-82. Epub 2012 Oct 26.

Laboratório de Espectrometria de Massas, Laboratório Nacional de Biociências, LNBio, Centro Nacional de Pesquisa em Energia e Materiais, Campinas, Brasil.

ADAM17, which is also known as TNFα-converting enzyme, is the major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins. How a membrane-anchored proteinase with an extracellular catalytic domain can be activated by inside-out regulation is not completely understood. We characterized thioredoxin-1 (Trx-1) as a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity. We induced the overexpression of the ADAM17 cytoplasmic domain in HEK293 cells, and ligands able to bind this domain were identified by MS after protein immunoprecipitation. Trx-1 was also validated as a ligand of the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins by immunoblotting, immunolocalization, and solid phase binding assay. In addition, using nuclear magnetic resonance, it was shown in vitro that the titration of the ADAM17 cytoplasmic domain promotes changes in the conformation of Trx-1. The MS analysis of the cross-linked complexes showed cross-linking between the two proteins by lysine residues. To further evaluate the functional role of Trx-1, we used a heparin-binding EGF shedding cell model and observed that the overexpression of Trx-1 in HEK293 cells could decrease the activity of ADAM17, activated by either phorbol 12-myristate 13-acetate or EGF. This study identifies Trx-1 as a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a potential candidate that could be involved in ADAM17 activity regulation.
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http://dx.doi.org/10.1074/jbc.M112.364513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522302PMC
December 2012

Bactericidal activity identified in 2S Albumin from sesame seeds and in silico studies of structure-function relations.

Protein J 2011 Jun;30(5):340-50

Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN Quadra, Modulo B, Brasília, Distrito Federal, Brazil.

Pathogenic bacteria constitute an important cause of hospital-acquired infections. However, the misuse of available bactericidal agents has led to the appearance of antibiotic-resistant strains. Thus, efforts to seek new antimicrobials with different action mechanisms would have an enormous impact. Here, a novel antimicrobial protein (SiAMP2) belonging to the 2S albumin family was isolated from Sesamum indicum kernels and evaluated against several bacteria and fungi. Furthermore, in silico analysis was conducted in order to identify conserved residues through other 2S albumin antimicrobial proteins (2S-AMPs). SiAMP2 specifically inhibited Klebsiella sp. Specific regions in the molecule surface where cationic (RR/RRRK) and hydrophobic (MEYWPR) residues are exposed and conserved were proposed as being involved in antimicrobial activity. This study reinforces the hypothesis that plant storage proteins might also play as pathogen protection providing an insight into the mechanism of action for this novel 2S-AMP and evolutionary relations between antimicrobial activity and 2S albumins.
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http://dx.doi.org/10.1007/s10930-011-9337-xDOI Listing
June 2011
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