1fbz

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[[Image:1fbz.gif|left|200px]]
[[Image:1fbz.gif|left|200px]]
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{{Structure
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<!--
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|PDB= 1fbz |SIZE=350|CAPTION= <scene name='initialview01'>1fbz</scene>, resolution 2.40&Aring;
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The line below this paragraph, containing "STRUCTURE_1fbz", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=CC1:{4-[2-ACETYLAMINO-2-(3-CARBAMOYL-2-CYCLOHEXYLMETHOXY-6,7,8,9-TETRAHYDRO-5H-BENZOCYCLOHEPTEN-5YLCARBAMOYL)-ETHYL]-2-PHOSPHONO-PHENYL}-PHOSPHONIC+ACID'>CC1</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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|DOMAIN=
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{{STRUCTURE_1fbz| PDB=1fbz | SCENE= }}
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|RELATEDENTRY=
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1fbz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1fbz OCA], [http://www.ebi.ac.uk/pdbsum/1fbz PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1fbz RCSB]</span>
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}}
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'''Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity'''
'''Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity'''
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[[Category: Weigele, M.]]
[[Category: Weigele, M.]]
[[Category: Yang, M.]]
[[Category: Yang, M.]]
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[[Category: nonpeptide inhibitor]]
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[[Category: Nonpeptide inhibitor]]
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[[Category: sh2 domain]]
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[[Category: Sh2 domain]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 16:09:09 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 20:19:54 2008''
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Revision as of 13:09, 2 May 2008

Image:1fbz.gif

Template:STRUCTURE 1fbz

Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity


Overview

Targeted disruption of the pp60(src) (Src) gene has implicated this tyrosine kinase in osteoclast-mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone-related diseases. Herein we describe the discovery of a nonpeptide inhibitor (AP22408) of Src that demonstrates in vivo antiresorptive activity. Based on a cocrystal structure of the noncatalytic Src homology 2 (SH2) domain of Src complexed with citrate [in the phosphotyrosine (pTyr) binding pocket], we designed 3',4'-diphosphonophenylalanine (Dpp) as a pTyr mimic. In addition to its design to bind Src SH2, the Dpp moiety exhibits bone-targeting properties that confer osteoclast selectivity, hence minimizing possible undesired effects on other cells that have Src-dependent activities. The chemical structure AP22408 also illustrates a bicyclic template to replace the post-pTyr sequence of cognate Src SH2 phosphopeptides such as Ac-pTyr-Glu-Glu-Ile (1). An x-ray structure of AP22408 complexed with Lck (S164C) SH2 confirmed molecular interactions of both the Dpp and bicyclic template of AP22408 as predicted from molecular modeling. Relative to the cognate phosphopeptide, AP22408 exhibits significantly increased Src SH2 binding affinity (IC(50) = 0.30 microM for AP22408 and 5.5 microM for 1). Furthermore, AP22408 inhibits rabbit osteoclast-mediated resorption of dentine in a cellular assay, exhibits bone-targeting properties based on a hydroxyapatite adsorption assay, and demonstrates in vivo antiresorptive activity in a parathyroid hormone-induced rat model.

About this Structure

1FBZ is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure-based design of an osteoclast-selective, nonpeptide src homology 2 inhibitor with in vivo antiresorptive activity., Shakespeare W, Yang M, Bohacek R, Cerasoli F, Stebbins K, Sundaramoorthi R, Azimioara M, Vu C, Pradeepan S, Metcalf C 3rd, Haraldson C, Merry T, Dalgarno D, Narula S, Hatada M, Lu X, van Schravendijk MR, Adams S, Violette S, Smith J, Guan W, Bartlett C, Herson J, Iuliucci J, Weigele M, Sawyer T, Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9373-8. PMID:10944210 Page seeded by OCA on Fri May 2 16:09:09 2008

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