1fbz

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
[[Image:1fbz.gif|left|200px]]
+
{{Seed}}
 +
[[Image:1fbz.png|left|200px]]
<!--
<!--
Line 9: Line 10:
{{STRUCTURE_1fbz| PDB=1fbz | SCENE= }}
{{STRUCTURE_1fbz| PDB=1fbz | SCENE= }}
-
'''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===
-
==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.
+
The line below this paragraph, {{ABSTRACT_PUBMED_10944210}}, adds the Publication Abstract to the page
 +
(as it appears on PubMed at http://www.pubmed.gov), where 10944210 is the PubMed ID number.
 +
-->
 +
{{ABSTRACT_PUBMED_10944210}}
==About this Structure==
==About this Structure==
Line 50: Line 54:
[[Category: Nonpeptide inhibitor]]
[[Category: Nonpeptide inhibitor]]
[[Category: Sh2 domain]]
[[Category: Sh2 domain]]
-
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 16:09:09 2008''
+
 
 +
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 1 03:01:19 2008''

Revision as of 00:01, 1 July 2008

Image:1fbz.png

Template:STRUCTURE 1fbz

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

Template:ABSTRACT PUBMED 10944210

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 Tue Jul 1 03:01:19 2008

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1fbz"
Personal tools