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PDBsum entry 1zlm
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Signaling protein
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PDB id
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1zlm
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References listed in PDB file
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Key reference
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Title
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Structure of the sh3 domain of human osteoclast-Stimulating factor at atomic resolution.
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Authors
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L.Chen,
Y.Wang,
D.Wells,
D.Toh,
H.Harold,
J.Zhou,
E.Digiammarino,
E.J.Meehan.
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Ref.
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Acta Crystallogr Sect F Struct Biol Cryst Commun, 2006,
62,
844-848.
[DOI no: ]
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PubMed id
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Abstract
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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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Figure 2.
Structure-based sequence alignment of hOSF-SH3 with the most
similar SH3 domains. The sequence numbers for the first and the
last residues are indicated. The positions of the [beta]-strands
in hOSF-SH3 are indicated by underlining the sequence and are
labeled. Residues that are highly conserved in the SH3-domain
family are indicated in bold type. Residues that are known to
form the proline-rich ligand-binding pocket are marked with an
asterisk. See Table 2 [triangle]
for protein PDB codes and references. Acta Crystallogr Sect F
Struct Biol Cryst Commun. 2006 September 1; 62(Pt 9): 844.
Published online 2006 August 18. doi: 10.1107/S1744309106030004.
Copyright [copyright] International Union of Crystallography
2006
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Figure 3.
Structure comparison and the peptide-binding model.
Stereoview of structural superposition of hOSF-SH3 (black) with
c-Crk-SH3 (red; PDB code 1cka) in complex with the proline-rich
peptide PPPALPPKK (green). Residues involved in peptide binding
are shown as stick models and the rest as C^[alpha] traces. The
peptide is also shown with stick models. For clarity, only the
termini and the key residues of hOSF-SH3 are labeled. Acta
Crystallogr Sect F Struct Biol Cryst Commun. 2006 September 1;
62(Pt 9): 844. Published online 2006 August 18. doi:
10.1107/S1744309106030004. Copyright [copyright] International
Union of Crystallography 2006
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The above figures are
reprinted
from an Open Access publication published by the IUCr:
Acta Crystallogr Sect F Struct Biol Cryst Commun
(2006,
62,
844-848)
copyright 2006.
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