4L19

Matrix metalloproteinase-13 complexed with selective inhibitor compound Q1

Summary for 4L19

• Entry DOI: 10.2210/pdb4l19/pdb
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (7 entities in total)
• Functional Keywords: metalloprotease, hydrolase, mmp-13, collagenase, exosite inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P45452
• Total number of polymer chains: 2
• Total formula weight: 40281.63

Authors

Minond, D.,Spicer, T.P.,Jiang, J.,Taylor, A.B.,Hart, P.J.,Roush, W.R.,Fields, G.B.,Hodder, P.S. (deposition date: 2013-06-02, release date: 2014-12-10, Last modification date: 2023-09-20)

Primary citation

Spicer, T.P.,Jiang, J.,Taylor, A.B.,Choi, J.Y.,Hart, P.J.,Roush, W.R.,Fields, G.B.,Hodder, P.S.,Minond, D.
Characterization of selective exosite-binding inhibitors of matrix metalloproteinase 13 that prevent articular cartilage degradation in vitro.
J.Med.Chem., 57:9598-9611, 2014

PubMed Abstract: Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans.

PubMed: 25330343
DOI: 10.1021/jm501284e

Experimental method

X-RAY DIFFRACTION (1.66 Å)