Document Detail

Structure analysis reveals the flexibility of the ADAMTS-5 active site.
MedLine Citation:
PMID:  21370305     Owner:  NLM     Status:  MEDLINE    
A ((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl) succinamide derivative (here referred to as Compound 12) shows significant activity toward many matrix metalloproteinases (MMPs), including MMP-2, MMP-8, MMP-9, and MMP-13. Modeling studies had predicted that this compound would not bind to ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs-5) due to its shallow S1' pocket. However, inhibition analysis revealed it to be a nanomolar inhibitor of both ADAMTS-4 and -5. The observed inconsistency was explained by analysis of crystallographic structures, which showed that Compound 12 in complex with the catalytic domain of ADAMTS-5 (cataTS5) exhibits an unusual conformation in the S1' pocket of the protein. This first demonstration that cataTS5 can undergo an induced conformational change in its active site pocket by a molecule like Compound 12 should enable the design of new aggrecanase inhibitors with better potency and selectivity profiles.
Huey-Sheng Shieh; Alfredo G Tomasselli; Karl J Mathis; Mark E Schnute; Scott S Woodard; Nicole Caspers; Jennifer M Williams; James R Kiefer; Grace Munie; Arthur Wittwer; Anne-Marie Malfait; Micky D Tortorella
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Protein science : a publication of the Protein Society     Volume:  20     ISSN:  1469-896X     ISO Abbreviation:  Protein Sci.     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-03-24     Completed Date:  2011-07-18     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  9211750     Medline TA:  Protein Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  735-44     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 The Protein Society.
Pfizer Global Research and Development, St. Louis, Missouri 63017, USA.
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MeSH Terms
ADAM Proteins / chemistry*
Amides / chemistry*
Catalytic Domain
Drug Design
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinases / metabolism
Models, Molecular
Molecular Sequence Data
Molecular Structure
Protein Conformation*
Reg. No./Substance:
0/Amides; 0/Matrix Metalloproteinase Inhibitors; 0/Succinates; 110-14-5/succinamide; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/ADAMTS5 protein, human; EC 3.4.24.-/Matrix Metalloproteinases

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