3KEJ

Crystal Structure of Human MMP-13 complexed with a (pyridin-4-yl)-2H-tetrazole compound

Summary for 3KEJ

• Entry DOI: 10.2210/pdb3kej/pdb
• Related: 3KEC 3KEK
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: s1' inhibitor, selective mmp-13 inhibitor, s1' specificity pocket, no contact to zn, collagen degradation, disease mutation, disulfide bond, extracellular matrix, glycoprotein, hydrolase, metal-binding, metalloprotease, protease, secreted, zymogen, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P45452
• Total number of polymer chains: 2
• Total formula weight: 38926.84

Authors

Shieh, H.-S.,Collins, B.,Schnute, M.E. (deposition date: 2009-10-26, release date: 2010-11-10, Last modification date: 2024-02-21)

Primary citation

Schnute, M.E.,O'Brien, P.M.,Nahra, J.,Morris, M.,Howard Roark, W.,Hanau, C.E.,Ruminski, P.G.,Scholten, J.A.,Fletcher, T.R.,Hamper, B.C.,Carroll, J.N.,Patt, W.C.,Shieh, H.S.,Collins, B.,Pavlovsky, A.G.,Palmquist, K.E.,Aston, K.W.,Hitchcock, J.,Rogers, M.D.,McDonald, J.,Johnson, A.R.,Munie, G.E.,Wittwer, A.J.,Man, C.F.,Settle, S.L.,Nemirovskiy, O.,Vickery, L.E.,Agawal, A.,Dyer, R.D.,Sunyer, T.
Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
Bioorg.Med.Chem.Lett., 20:576-580, 2010

PubMed Abstract: Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

PubMed: 20005097
DOI: 10.1016/j.bmcl.2009.11.081

Experimental method

X-RAY DIFFRACTION (2.3 Å)