1fbz
From Proteopedia
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| - | [[Image:1fbz.gif|left|200px]] | + | [[Image:1fbz.gif|left|200px]] |
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| - | '''Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity''' | + | {{Structure |
| + | |PDB= 1fbz |SIZE=350|CAPTION= <scene name='initialview01'>1fbz</scene>, resolution 2.40Å | ||
| + | |SITE= | ||
| + | |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> | ||
| + | |ACTIVITY= [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] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1FBZ is a [ | + | 1FBZ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1FBZ OCA]. |
==Reference== | ==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:[http:// | + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/10944210 10944210] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: sh2 domain]] | [[Category: sh2 domain]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 11:07:08 2008'' |
Revision as of 09:07, 20 March 2008
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| , resolution 2.40Å | |||||||
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| Ligands: | |||||||
| Activity: | Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Structure-based design of a novel, osteoclast-selective, nonpeptide Src SH2 inhibitor with in vivo anti-resorptive activity
Contents |
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.
Disease
Known disease associated with this structure: SCID due to LCK deficiency OMIM:[153390]
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 Thu Mar 20 11:07:08 2008
Categories: Homo sapiens | Single protein | Transferase | Adams, S. | Bartlett, C. | Bohacek, R. | Cerasoli, F. | Dalgarno, D. | Guan, W. | Haraldson, C. | Hatada, M. | Herson, J. | Iuliucci, J. | Lu, X. | Merry, T. | Metcalf, C. | Narula, S. | Pradeepan, S. | Sawyer, T. | Schravendijk, M R.Van. | Shakespeare, W. | Smith, J. | Stebbis, K. | Sundaramoorthi, R. | Violette, S. | Vu, C. | Weigele, M. | Yang, M. | CC1 | Nonpeptide inhibitor | Sh2 domain
