3LJT: Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with an Amino-2-indanol compound

Citation:
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.
PDB ID: 3LJTDownload
MMDB ID: 81135
PDB Deposition Date: 2010/1/26
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Similar Structures:
Biological Unit for 3LJT: monomeric; determined by author and by software (PISA)
Molecular Components in 3LJT
Label Count Molecule
Protein (1 molecule)
1
a Disintegrin and Metalloproteinase With Thrombospondin Motifs 5(Gene symbol: ADAMTS5)
Molecule annotation
Chemicals (6 molecules)
1
1
2
1
3
1
4
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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