4WKE
Crystal structure of human ADAMTS-4 in complex with inhibitor 5-chloro-N-{[(4R)-2,5-dioxo-4-(1,3-thiazol-2-yl)imidazolidin-4-yl]methyl}-1-benzofuran-2-carboxamide (compound 10)
Summary for 4WKE
| Entry DOI | 10.2210/pdb4wke/pdb |
| Related | 4WK7 4WKI |
| Descriptor | A disintegrin and metalloproteinase with thrombospondin motifs 4, ZINC ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | metalloprotease, osteoarthritis, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Cellular location | Secreted, extracellular space, extracellular matrix : O75173 |
| Total number of polymer chains | 1 |
| Total formula weight | 26247.53 |
| Authors | Durbin, J.D. (deposition date: 2014-10-02, release date: 2014-12-10, Last modification date: 2024-10-23) |
| Primary citation | Durham, T.B.,Klimkowski, V.J.,Rito, C.J.,Marimuthu, J.,Toth, J.L.,Liu, C.,Durbin, J.D.,Stout, S.L.,Adams, L.,Swearingen, C.,Lin, C.,Chambers, M.G.,Thirunavukkarasu, K.,Wiley, M.R. Identification of potent and selective hydantoin inhibitors of aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical and surgical models of osteoarthritis. J.Med.Chem., 57:10476-10485, 2014 Cited by PubMed Abstract: A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats. PubMed: 25415648DOI: 10.1021/jm501522n PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.62 Å) |
Structure validation
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