Structure analysis reveals the flexibility of the ADAMTS-5 active site.

Autor: Shieh HS; Pfizer Global Research and Development, St. Louis, Missouri 63017, USA. shiehouse@sbcglobal.net, Tomasselli AG, Mathis KJ, Schnute ME, Woodard SS, Caspers N, Williams JM, Kiefer JR, Munie G, Wittwer A, Malfait AM, Tortorella MD
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2011 Apr; Vol. 20 (4), pp. 735-44.
DOI: 10.1002/pro.606
Abstrakt: 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.
(Copyright © 2011 The Protein Society.)
Databáze: MEDLINE
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