4WKI

Crystal structure of human ADAMTS-4 in complex with inhibitor 5-CHLORO-N-{[(4S)-4-(1-METHYL-1H-IMIDAZOL-2-YL)-2,5-DIOXOIMIDAZOLIDIN-4-YL]METHYL}-1-BENZOFURAN-2-CARBOXAMIDE (compound 11)

4WKI の概要

• エントリーDOI: 10.2210/pdb4wki/pdb
• 関連するPDBエントリー: 4WK7 4WKE
• 分子名称: A disintegrin and metalloproteinase with thrombospondin motifs 4, ZINC ION, CALCIUM ION, ... (6 entities in total)
• 機能のキーワード: metalloprotease, osteoarthritis, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Secreted, extracellular space, extracellular matrix : O75173
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 26120.37

構造登録者

Durbin, J.D. (登録日: 2014-10-02, 公開日: 2014-12-10, 最終更新日: 2024-10-16)

主引用文献

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

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: 25415648
DOI: 10.1021/jm501522n

実験手法

X-RAY DIFFRACTION (1.6 Å)