3LJT

Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with an Amino-2-indanol compound

Summary for 3LJT

• Entry DOI: 10.2210/pdb3ljt/pdb
• Related: 3HY9 3HYG 3LJZ
• Descriptor: A disintegrin and metalloproteinase with thrombospondin motifs 5, (2R)-2-[4-(1,3-benzodioxol-5-yl)benzyl]-N~4~-hydroxy-N~1~-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: alpha/beta structure, central five stranded beta-sheet, cleavage on pair of basic residues, disulfide bond, extracellular matrix, glycoprotein, metal-binding, metalloprotease, protease, secreted, zymogen, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : Q9UNA0
• Total number of polymer chains: 1
• Total formula weight: 24827.43

Authors

Shieh, H.-S.,Williams, J.M.,Caspers, N. (deposition date: 2010-01-26, release date: 2010-03-31, Last modification date: 2024-11-20)

Primary citation

Shieh, H.S.,Tomasselli, A.G.,Mathis, K.J.,Schnute, M.E.,Woodard, S.S.,Caspers, N.,Williams, J.M.,Kiefer, J.R.,Munie, G.,Wittwer, A.,Malfait, A.M.,Tortorella, M.D.
Structure analysis reveals the flexibility of the ADAMTS-5 active site.
Protein Sci., 20:735-744, 2011

PubMed Abstract: 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.

PubMed: 21370305
DOI: 10.1002/pro.606

Experimental method

X-RAY DIFFRACTION (1.6 Å)