Publications by authors named "Bhamini Vaidialingam"

3 Publications

  • Page 1 of 1

Crystal structure of human GDF11.

Acta Crystallogr F Struct Biol Commun 2016 Mar 16;72(Pt 3):160-4. Epub 2016 Feb 16.

Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, USA.

Members of the TGF-β family of proteins are believed to play critical roles in cellular signaling processes such as those involved in muscle differentiation. The extent to which individual family members have been characterized and linked to biological function varies greatly. The role of myostatin, also known as growth differentiation factor 8 (GDF8), as an inhibitor of muscle differentiation is well understood through genetic linkages. In contrast, the role of growth differentiation factor 11 (GDF11) is much less well understood. In humans, the mature forms of GDF11 and myostatin are over 94% identical. In order to understand the role that the small differences in sequence may play in the differential signaling of these molecules, the crystal structure of GDF11 was determined to a resolution of 1.50 Å. A comparison of the GDF11 structure with those of other family members reveals that the canonical TGF-β domain fold is conserved. A detailed structural comparison of GDF11 and myostatin shows that several of the differences between these proteins are likely to be localized at interfaces that are critical for the interaction with downstream receptors and inhibitors.
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http://dx.doi.org/10.1107/S2053230X16001588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774873PMC
March 2016

mTOR kinase structure, mechanism and regulation.

Nature 2013 May 1;497(7448):217-23. Epub 2013 May 1.

Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

The mammalian target of rapamycin (mTOR), a phosphoinositide 3-kinase-related protein kinase, controls cell growth in response to nutrients and growth factors and is frequently deregulated in cancer. Here we report co-crystal structures of a complex of truncated mTOR and mammalian lethal with SEC13 protein 8 (mLST8) with an ATP transition state mimic and with ATP-site inhibitors. The structures reveal an intrinsically active kinase conformation, with catalytic residues and a catalytic mechanism remarkably similar to canonical protein kinases. The active site is highly recessed owing to the FKBP12-rapamycin-binding (FRB) domain and an inhibitory helix protruding from the catalytic cleft. mTOR-activating mutations map to the structural framework that holds these elements in place, indicating that the kinase is controlled by restricted access. In vitro biochemistry shows that the FRB domain acts as a gatekeeper, with its rapamycin-binding site interacting with substrates to grant them access to the restricted active site. Rapamycin-FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and conformational changes that underlie inhibitor potency and specificity.
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http://dx.doi.org/10.1038/nature12122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4512754PMC
May 2013

Crystal structure of Escherichia coli polynucleotide phosphorylase core bound to RNase E, RNA and manganese: implications for catalytic mechanism and RNA degradosome assembly.

J Mol Biol 2009 May 24;389(1):17-33. Epub 2009 Mar 24.

Department of Biochemistry, University of Cambridge, UK.

Polynucleotide phosphorylase (PNPase) is a processive exoribonuclease that contributes to messenger RNA turnover and quality control of ribosomal RNA precursors in many bacterial species. In Escherichia coli, a proportion of the PNPase is recruited into a multi-enzyme assembly, known as the RNA degradosome, through an interaction with the scaffolding domain of the endoribonuclease RNase E. Here, we report crystal structures of E. coli PNPase complexed with the recognition site from RNase E and with manganese in the presence or in the absence of modified RNA. The homotrimeric PNPase engages RNase E on the periphery of its ring-like architecture through a pseudo-continuous anti-parallel beta-sheet. A similar interaction pattern occurs in the structurally homologous human exosome between the Rrp45 and Rrp46 subunits. At the centre of the PNPase ring is a tapered channel with an adjustable aperture where RNA bases stack on phenylalanine side chains and trigger structural changes that propagate to the active sites. Manganese can substitute for magnesium as an essential co-factor for PNPase catalysis, and our crystal structure of the enzyme in complex with manganese suggests how the metal is positioned to stabilise the transition state. We discuss the implications of these structural observations for the catalytic mechanism of PNPase, its processive mode of action, and its assembly into the RNA degradosome.
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http://dx.doi.org/10.1016/j.jmb.2009.03.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723993PMC
May 2009