1XUC

Matrix metalloproteinase-13 complexed with non-zinc binding inhibitor

Summary for 1XUC

• Entry DOI: 10.2210/pdb1xuc/pdb
• Related: 1XUD 1XUR
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: matrix metalloproteinase, non-zinc binding inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix (Probable): P45452
• Total number of polymer chains: 2
• Total formula weight: 39641.59

Authors

Engel, C.K.,Wendt, K.U. (deposition date: 2004-10-26, release date: 2005-10-26, Last modification date: 2024-03-13)

Primary citation

Engel, C.K.,Pirard, B.,Schimanski, S.,Kirsch, R.,Habermann, J.,Klingler, O.,Schlotte, V.,Weithmann, K.U.,Wendt, K.U.
Structural basis for the highly selective inhibition of MMP-13
Chem.Biol., 12:181-189, 2005

PubMed Abstract: Inhibitors for matrix metalloproteinases (MMPs) are under investigation for the treatment of cancer, arthritis, and cardiovascular disease. Here, we report a class of highly selective MMP-13 inhibitors (pyrimidine dicarboxamides) that exhibit no detectable activity against other MMPs. The high-resolution X-ray structures of three molecules of this series bound to MMP-13 reveal a novel binding mode characterized by the absence of interactions between the inhibitors and the catalytic zinc. The inhibitors bind in the S1' pocket and extend into an additional S1' side pocket, which is unique to MMP-13. We analyze the determinants for selectivity and describe the rational design of improved compounds with low nanomolar affinity.

PubMed: 15734645
DOI: 10.1016/j.chembiol.2004.11.014

Experimental method

X-RAY DIFFRACTION (1.7 Å)