Publications by authors named "Ulli Rothweiler"

19 Publications

  • Page 1 of 1

2.09 Å Resolution structure of E. coli HigBA toxin-antitoxin complex reveals an ordered DNA-binding domain and intrinsic dynamics in antitoxin.

Biochem J 2020 10;477(20):4001-4019

Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India.

The toxin-antitoxin (TA) systems are small operon systems that are involved in important physiological processes in bacteria such as stress response and persister cell formation. Escherichia coli HigBA complex belongs to the type II TA systems and consists of a protein toxin called HigB and a protein antitoxin called HigA. The toxin HigB is a ribosome-dependent endoribonuclease that cleaves the translating mRNAs at the ribosome A site. The antitoxin HigA directly binds the toxin HigB, rendering the HigBA complex catalytically inactive. The existing biochemical and structural studies had revealed that the HigBA complex forms a heterotetrameric assembly via dimerization of HigA antitoxin. Here, we report a high-resolution crystal structure of E. coli HigBA complex that revealed a well-ordered DNA binding domain in HigA antitoxin. Using SEC-MALS and ITC methods, we have determined the stoichiometry of complex formation between HigBA and a 33 bp DNA and report that HigBA complex as well as HigA homodimer bind to the palindromic DNA sequence with nano molar affinity. Using E. coli growth assays, we have probed the roles of key, putative active site residues in HigB. Spectroscopic methods (CD and NMR) and molecular dynamics simulations study revealed intrinsic dynamic in antitoxin in HigBA complex, which may explain the large conformational changes in HigA homodimer in free and HigBA complexes observed previously. We also report a truncated, heterodimeric form of HigBA complex that revealed possible cleavage sites in HigBA complex, which can have implications for its cellular functions.
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http://dx.doi.org/10.1042/BCJ20200363DOI Listing
October 2020

The crystal structure of haemoglobin from Atlantic cod.

Acta Crystallogr F Struct Biol Commun 2019 Aug 16;75(Pt 8):537-542. Epub 2019 Jul 16.

Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Faculty of Science and Technology, NO-4036 Stavanger, Norway.

The crystal structure of haemoglobin from Atlantic cod has been solved to 2.54 Å resolution. The structure consists of two tetramers in the crystallographic asymmetric unit. The structure of haemoglobin obtained from one individual cod suggests polymorphism in the tetrameric assembly.
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http://dx.doi.org/10.1107/S2053230X1900904XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688665PMC
August 2019

The crystal structure of the N-acetylglucosamine 2-epimerase from Nostoc sp. KVJ10 reveals the true dimer.

Acta Crystallogr D Struct Biol 2019 Jan 8;75(Pt 1):90-100. Epub 2019 Jan 8.

The Norwegian Structural Biology Centre (NorStruct), Department of Chemistry, UiT - The Arctic University of Norway, 9037 Tromsø, Norway.

N-Acetylglucosamine 2-epimerases (AGEs) catalyze the interconversion of N-acetylglucosamine and N-acetylmannosamine. They can be used to perform the first step in the synthesis of sialic acid from N-acetylglucosamine, which makes the need for efficient AGEs a priority. This study presents the structure of the AGE from Nostoc sp. KVJ10 collected in northern Norway, referred to as nAGE10. It is the third AGE structure to be published to date, and the first one in space group P422. The nAGE10 monomer folds as an (α/α) barrel in a similar manner to that of the previously published AGEs, but the crystal did not contain the dimers that have previously been reported. The previously proposed `back-to-back' assembly involved the face of the AGE monomer where the barrel helices are connected by small loops. Instead, a `front-to-front' dimer was found in nAGE10 involving the long loops that connect the barrel helices at this end. This assembly is also present in the other AGE structures, but was attributed to crystal packing, even though the `front' interface areas are larger and are more conserved than the `back' interface areas. In addition, the front-to-front association allows a better explanation of the previously reported observations considering surface cysteines. Together, these results indicate that the `front-to-front' dimer is the most probable biological assembly for AGEs.
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http://dx.doi.org/10.1107/S2059798318017047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333288PMC
January 2019

Novel Scaffolds for Dual Specificity Tyrosine-Phosphorylation-Regulated Kinase (DYRK1A) Inhibitors.

J Med Chem 2018 09 23;61(17):7560-7572. Epub 2018 Aug 23.

The Norwegian Structural Biology Centre, Department of Chemistry , UiT The Arctic University of Norway , N-9037 Tromsø , Norway.

DYRK1A is one of five members of the dual-specificity tyrosine (Y) phosphorylation-regulated kinase (DYRK) family. The DYRK1A gene is located in the Down syndrome critical region and regulates cellular processes related to proliferation and differentiation of neuronal progenitor cells during early development. This has focused research on its role in neuronal degenerative diseases, including Alzheimer's and Down syndrome. Recent studies have also shown a possible role of DYRK1A in diabetes. Here we report a variety of scaffolds not generally known for DYRK1A inhibition, demonstrating their effects in in vitro assays and also in cell cultures. These inhibitors effectively block the tau phosphorylation that is a hallmark of Alzheimer's disease. The crystal structures of these inhibitors support the design of optimized and novel therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01847DOI Listing
September 2018

Structure and function of a CE4 deacetylase isolated from a marine environment.

PLoS One 2017 6;12(11):e0187544. Epub 2017 Nov 6.

Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences (NMBU), Ås, Norway.

Chitin, a polymer of β(1-4)-linked N-acetylglucosamine found in e.g. arthropods, is a valuable resource that may be used to produce chitosan and chitooligosaccharides, two compounds with considerable industrial and biomedical potential. Deacetylating enzymes may be used to tailor the properties of chitin and its derived products. Here, we describe a novel CE4 enzyme originating from a marine Arthrobacter species (ArCE4A). Crystal structures of this novel deacetylase were determined, with and without bound chitobiose [(GlcNAc)2], and refined to 2.1 Å and 1.6 Å, respectively. In-depth biochemical characterization showed that ArCE4A has broad substrate specificity, with higher activity against longer oligosaccharides. Mass spectrometry-based sequencing of reaction products generated from a fully acetylated pentamer showed that internal sugars are more prone to deacetylation than the ends. These enzyme properties are discussed in the light of the structure of the enzyme-ligand complex, which adds valuable information to our still rather limited knowledge on enzyme-substrate interactions in the CE4 family.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673215PMC
November 2017

Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules.

J Med Chem 2016 11 21;59(21):9814-9824. Epub 2016 Oct 21.

Pharmasum Therapeutics AS , Smørblomstvn. 36, N-9102 Kvaløysletta, Norway.

DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01086DOI Listing
November 2016

Assessing protein kinase target similarity: Comparing sequence, structure, and cheminformatics approaches.

Biochim Biophys Acta 2015 Oct 19;1854(10 Pt B):1605-16. Epub 2015 May 19.

The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway. Electronic address:

In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward "personalized medicine" with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the "calibration" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
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http://dx.doi.org/10.1016/j.bbapap.2015.05.004DOI Listing
October 2015

The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine.

Acta Crystallogr D Biol Crystallogr 2015 May 25;71(Pt 5):1207-15. Epub 2015 Apr 25.

Department of Chemistry, The Norwegian Structural Biology Centre, The Arctic University of Norway, 9037 Tromsø, Norway.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. The DYRK kinases are very unusual with respect to the sequence of the catalytic loop, in which the otherwise highly conserved arginine of the HRD motif is replaced by a cysteine. This replacement, along with the proximity of a potential disulfide-bridge partner from the activation segment, implies a potential for redox control of DYRK family activities. Here, the crystal structure of DYRK1A bound to PKC412 is reported, showing the formation of the disulfide bridge and associated conformational changes of the activation loop. The DYRK kinases represent emerging drug targets for several neurological diseases as well as cancer. The observation of distinct activation states may impact strategies for drug targeting. In addition, the characterization of PKC412 binding offers new insights for DYRK inhibitor discovery.
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http://dx.doi.org/10.1107/S1399004715005106DOI Listing
May 2015

Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors.

Eur J Med Chem 2015 Apr 25;94:140-8. Epub 2015 Feb 25.

Lytix Biopharma AS, P.O. Box 6447, Tromsø Science Park, N-9294 Tromsø, Norway; Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway. Electronic address:

D-Luciferin is widely used as a substrate in luciferase catalysed bioluminescence assays for in vitro studies. However, little is known about cross reactivity and potential interference of D-luciferin with other enzymes. We serendipitously found that firefly luciferin inhibited the CDK2/Cyclin A protein kinase. Inhibition profiling of D-luciferin over a 103-protein kinase panel showed significant inhibition of a small set of protein kinases, in particular the DYRK-family, but also other members of the CMGC-group, including ERK8 and CK2. Inhibition profiling on a 16-member focused library derived from D-luciferin confirms that D-luciferin represents a DYRK-selective chemotype of fragment-like molecular weight. Thus, observation of its inhibitory activity and the initial SAR information reported here promise to be useful for further design of protein kinase inhibitors with related scaffolds.
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http://dx.doi.org/10.1016/j.ejmech.2015.02.035DOI Listing
April 2015

Enzyme-adenylate structure of a bacterial ATP-dependent DNA ligase with a minimized DNA-binding surface.

Acta Crystallogr D Biol Crystallogr 2014 Nov 29;70(Pt 11):3043-56. Epub 2014 Oct 29.

NorStruct, Department of Chemistry, UiT The Arctic University of Norway, N-9037 Tromsø, Norway.

DNA ligases are a structurally diverse class of enzymes which share a common catalytic core and seal breaks in the phosphodiester backbone of double-stranded DNA via an adenylated intermediate. Here, the structure and activity of a recombinantly produced ATP-dependent DNA ligase from the bacterium Psychromonas sp. strain SP041 is described. This minimal-type ligase, like its close homologues, is able to ligate singly nicked double-stranded DNA with high efficiency and to join cohesive-ended and blunt-ended substrates to a more limited extent. The 1.65 Å resolution crystal structure of the enzyme-adenylate complex reveals no unstructured loops or segments, and suggests that this enzyme binds the DNA without requiring full encirclement of the DNA duplex. This is in contrast to previously characterized minimal DNA ligases from viruses, which use flexible loop regions for DNA interaction. The Psychromonas sp. enzyme is the first structure available for the minimal type of bacterial DNA ligases and is the smallest DNA ligase to be crystallized to date.
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http://dx.doi.org/10.1107/S1399004714021099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220977PMC
November 2014

Structural origins of AGC protein kinase inhibitor selectivities: PKA as a drug discovery tool.

Biol Chem 2012 Oct;393(10):1121-9

Norwegian Structural Biology Center, Department of Chemistry, University of Tromsø, N-9012 Tromsø, Norway.

The era of structure-based protein kinase inhibitor design began in the early 1990s with the determination of crystal structures of protein kinase A (PKA, or cyclic AMP-dependent kinase). Although many other protein kinases have since been extensively characterized, PKA remains a prototype for studies of protein kinase active conformations. It serves well as a model for the structural properties of AGC subfamily protein kinases, clarifying inhibitor selectivity profiles. Its reliable expression, constitutive activity, simple domain structure, and reproducible crystallizability have also made it a useful surrogate for the discovery of inhibitors of both established and emerging AGC kinase targets.
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http://dx.doi.org/10.1515/hsz-2012-0248DOI Listing
October 2012

p38α MAP kinase dimers with swapped activation segments and a novel catalytic loop conformation.

J Mol Biol 2011 Aug 15;411(2):474-85. Epub 2011 Jun 15.

Department of Chemistry, The Norwegian Structural Biology Centre, University of Tromsø, 9037 Tromsø, Norway.

Many protein kinase functions, including autophosphorylation in trans, require dimerization, possibly by activation segment exchange. Such dimers have been reported for a few autophosphorylating protein kinases, but not for mitogen-activated protein kinases (MAPKs). Activation of MAPKs proceeds not only via the well-characterized action of dual T/Y specificity MAPK kinases, phosphorylating both residues of the MAPK TxY activation loop motif, but also via a noncanonical activation pathway triggered by phosphorylation at Tyr323 and homodimerization. Here, we report the 2. 7-Å-resolution structure of p38α MAPK from Salmo salar in a novel domain-swapped homodimeric form. The tyrosines of the conserved sequence YxAPE anchor the swapped activation segments in a configuration suitable for autophosphorylation in trans and provide a model for the noncanonical pathway. In the dimer, a structural unit containing Tyr323 is formed at a dimerization contact region that stabilizes the HRD catalytic loop in a unique inactive geometry. This feature is consistent with the requirement of Tyr323 phosphorylation for the initiation of the noncanonical pathway. Despite the interacting surface of more than 2600 Å(2), the dimer is not obligate, as gel filtration shows the dimerization to occur only at relatively high concentrations. The transition from monomer to dimer involves a relatively simple hinged displacement of helix EF and adjacent residues. Thus, dimer formation is likely to be transient, compatible with functional requirements for autophosphorylation, allowing further modulation, for example, by scaffolding mechanisms.
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http://dx.doi.org/10.1016/j.jmb.2011.06.013DOI Listing
August 2011

Shugoshin is a Mad1/Cdc20-like interactor of Mad2.

EMBO J 2011 Jun 10;30(14):2868-80. Epub 2011 Jun 10.

Department of Genetics, University of Bayreuth, Bayreuth, Germany.

Mammalian centromeric cohesin is protected from phosphorylation-dependent displacement in mitotic prophase by shugoshin-1 (Sgo1), while shugoshin-2 (Sgo2) protects cohesin from separase-dependent cleavage in meiosis I. In higher eukaryotes, progression and faithful execution of both mitosis and meiosis are controlled by the spindle assembly checkpoint, which delays anaphase onset until chromosomes have achieved proper attachment to microtubules. According to the so-called template model, Mad1-Mad2 complexes at unattached kinetochores instruct conformational change of soluble Mad2, thus catalysing Mad2 binding to its target Cdc20. Here, we show that human Sgo2, but not Sgo1, specifically interacts with Mad2 in a manner that strongly resembles the interactions of Mad2 with Mad1 or Cdc20. Sgo2 contains a Mad1/Cdc20-like Mad2-interaction motif and competes with Mad1 and Cdc20 for binding to Mad2. NMR and biochemical analyses show that shugoshin binding induces similar conformational changes in Mad2 as do Mad1 or Cdc20. Mad2 binding regulates fine-tuning of Sgo2's sub-centromeric localization. Mad2 binding is conserved in the only known Xenopus laevis shugoshin homologue and, compatible with a putative meiotic function, the interaction occurs in oocytes.
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http://dx.doi.org/10.1038/emboj.2011.187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160248PMC
June 2011

NMR screening for lead compounds using tryptophan-mutated proteins.

J Med Chem 2008 Aug 5;51(16):5035-42. Epub 2008 Aug 5.

Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.

NMR-based drug screening methods provide the most reliable characterization of binding propensities of ligands to their target proteins. They are, however, one of the least effective methods in terms of the amount of protein required and the time needed for acquiring an NMR experiment. We show here that the introduction of tryptophan to proteins permits rapid screening by monitoring a simple 1D proton NMR signal of the NH side chain ((N)H(epsilon)) of the tryptophan. The method could also provide quantitative characterization of the antagonist-protein and antagonist-protein-protein interactions in the form of KDs and fractions of the released proteins from their mutual binding. We illustrate the method with the lead compounds that block the Mdm2-p53 interaction and by studying inhibitors that bind to cyclin-dependent kinase 2 (CDK2).
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http://dx.doi.org/10.1021/jm8002813DOI Listing
August 2008

Isoquinolin-1-one inhibitors of the MDM2-p53 interaction.

ChemMedChem 2008 Jul;3(7):1118-28

Max Planck Institute for Biochemistry, 82152 Martinsried, Germany.

p53 has been at the centre of attention for drug design since the discovery of its growth-suppressive and pro-apoptotic activity. Herein we report the design and characterisation of a new class of isoquinolinone inhibitors of the MDM2-p53 interaction. Our identification of druglike and selective inhibitors of this protein-protein interaction included a straightforward in silico compound-selection process, a recently reported NMR spectroscopic approach for studying the MDM2-p53 interaction, and selectivity screening assays using cells with the same genetic background. The selected inhibitors were all able to induce apoptosis and the expression of p53-related genes, but only the isoquinolin-1-one-based inhibitors stabilised p53. Our NMR experiments give a persuading explanation for these results, showing that isoquinolin-1-one derivates are able to dissociate the preformed MDM2-p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods provides a framework for the discovery of protein interaction inhibitors as a promising starting point for further drug design.
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http://dx.doi.org/10.1002/cmdc.200800025DOI Listing
July 2008

Molecular basis for the inhibition of p53 by Mdmx.

Cell Cycle 2007 Oct 12;6(19):2386-92. Epub 2007 Oct 12.

Max Planck Institute for Biochemistry, Martinsried, Germany.

The oncoprotein Mdm2, and the recently intensely studied, homologues protein Mdmx, are principal negative regulators of the p53 tumor suppressor. The mechanisms by which they regulate the stability and activity of p53 are not fully established. We have determined the crystal structure of the N-terminal domain of Mdmx bound to a 15-residue p53 peptide. The structure reveals that although the principle features of the Mdm2-p53 interaction are preserved in the Mdmx-p53 complex, the Mdmx hydrophobic cleft on which the p53 peptide binds is significantly altered: a part of the cleft is blocked by sidechains of Met and Tyr of the p53-binding pocket of Mdmx. Thus specific inhibitors of Mdm2-p53 would not be optimal for binding to Mdmx. Our binding assays show indeed that nutlins, the newly discovered, potent antagonists of the Mdm2-p53 interaction, are not capable to efficiently disrupt the Mdmx-p53 interaction. To achieve full activation of p53 in tumor cells, compounds that are specific for Mdmx are necessary to complement the Mdm2 specific binders.
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http://dx.doi.org/10.4161/cc.6.19.4740DOI Listing
October 2007

An NMR-based antagonist induced dissociation assay for targeting the ligand-protein and protein-protein interactions in competition binding experiments.

J Med Chem 2007 Sep 16;50(18):4382-7. Epub 2007 Aug 16.

Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.

We present an NMR-based antagonist induced dissociation assay (AIDA) for validation of inhibitor action on protein-protein interactions. As opposed to many standard NMR methods, AIDA directly validates the inhibitor potency in an in vitro NMR competition binding experiment. AIDA requires a large protein fragment (larger than 30 kDa) to bind to a small reporter protein (less than 20 kDa). We show here that a small fragment of a protein fused to glutathione S-transferase (GST) can effectively substitute the large protein component. We successfully used a GST-tagged N-terminal 73-residue p53 domain for binding studies with the human MDM2 protein. Other interactions we studied involved complexes of CDK2, cyclin A, p27, and the retinoblastoma protein. All these proteins play a key role in the cell division cycle, are associated with tumorigenesis, and are thus the subject of anticancer therapy strategies.
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http://dx.doi.org/10.1021/jm070365vDOI Listing
September 2007

Monitoring the effects of antagonists on protein-protein interactions with NMR spectroscopy.

J Am Chem Soc 2005 Sep;127(38):13220-6

Max Planck Institute for Biochemistry, D-82152 Martinsried, Germany.

We describe an NMR method that directly monitors the influence of ligands on protein-protein interactions. For a two-protein interaction complex, the size of one component should be small enough (less than ca. 15 kDa) to provide a good quality (15)N((13)C) HSQC spectrum after (15)N((13)C) labeling. The size of the second unlabeled component should be large enough so that the molecular weight of the preformed complex is larger than ca. 40 kDa. When the smaller protein binds to a larger one, broadening of NMR resonances results in the disappearance of most of its cross-peaks in the HSQC spectrum. Addition of an antagonist that can dissociate the complex would restore the HSQC spectrum of the smaller component. The method directly shows whether an antagonist releases proteins in their wild-type folded states or whether it induces their denaturation, partial unfolding, or precipitation. We illustrate the method by studying lead compounds that have recently been reported to block the MDM2-p53 interaction. Activation of p53 in tumor cells by inhibiting its interaction with MDM2 offers new strategy for cancer therapy.
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http://dx.doi.org/10.1021/ja052143xDOI Listing
September 2005