1zlm Citations

Structure of the SH3 domain of human osteoclast-stimulating factor at atomic resolution.

Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62 844-8 (2006)
Cited: 3 times
EuropePMC logo PMID: 16946461

Abstract

Osteoclast-stimulating factor (OSF) is an intracellular signaling protein, produced by osteoclasts themselves, that enhances osteoclast formation and bone resorption. It is thought to act via an Src-related signaling pathway and contains SH3 and ankyrin-repeat domains which are involved in protein-protein interactions. As part of a structure-based anti-bone-loss drug-design program, the atomic resolution X-ray structure of the recombinant human OSF SH3 domain (hOSF-SH3) has been determined. The domain, residues 12-72, yielded crystals that diffracted to the ultrahigh resolution of 1.07 A. The overall structure shows a characteristic SH3 fold consisting of two perpendicular beta-sheets that form a beta-barrel. Structure-based sequence alignment reveals that the putative proline-rich peptide-binding site of hOSF-SH3 consists of (i) residues that are highly conserved in the SH3-domain family, including residues Tyr21, Phe23, Trp49, Pro62, Asn64 and Tyr65, and (ii) residues that are less conserved and/or even specific to hOSF, including Thr22, Arg26, Thr27, Glu30, Asp46, Thr47, Asn48 and Leu60, which might be key to designing specific inhibitors for hOSF to fight osteoporosis and related bone-loss diseases. There are a total of 13 well defined water molecules forming hydrogen bonds with the above residues in and around the peptide-binding pocket. Some of those water molecules might be important for drug-design approaches. The hOSF-SH3 structure at atomic resolution provides an accurate framework for structure-based design of its inhibitors.

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Articles citing this publication (2)

  1. Targeted disruption of leucine-rich repeat kinase 1 but not leucine-rich repeat kinase 2 in mice causes severe osteopetrosis. Xing W, Liu J, Cheng S, Vogel P, Mohan S, Brommage R. J. Bone Miner. Res. 28 1962-1974 (2013)
  2. Crystal structure of human osteoclast stimulating factor. Tong S, Zhou H, Gao Y, Zhu Z, Zhang X, Teng M, Niu L. Proteins 75 245-251 (2009)