2OW2

MMP-9 active site mutant with difluoro butanoic acid inhibitor

Summary for 2OW2

• Entry DOI: 10.2210/pdb2ow2/pdb
• Related: 1GKC 1GKD
• Descriptor: Matrix metalloproteinase-9 (MMP-9) (92 kDa type IV collagenase) (92 kDa gelatinase) (Gelatinase B) (GELB), ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: matrix metalloproteinase, s1-prime pocket, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted, extracellular space, extracellular matrix : P14780
• Total number of polymer chains: 2
• Total formula weight: 36913.19

Authors

Tochowicz, A.,Bode, W.,Maskos, K.,Goettig, P. (deposition date: 2007-02-15, release date: 2007-06-19, Last modification date: 2023-08-30)

Primary citation

Tochowicz, A.,Maskos, K.,Huber, R.,Oltenfreiter, R.,Dive, V.,Yiotakis, A.,Zanda, M.,Bode, W.,Goettig, P.
Crystal Structures of MMP-9 Complexes with Five Inhibitors: Contribution of the Flexible Arg424 Side-chain to Selectivity.
J.Mol.Biol., 371:989-1006, 2007

PubMed Abstract: Human matrix metalloproteinase 9 (MMP-9), also called gelatinase B, is particularly involved in inflammatory processes, bone remodelling and wound healing, but is also implicated in pathological processes such as rheumatoid arthritis, atherosclerosis, tumour growth, and metastasis. We have prepared the inactive E402Q mutant of the truncated catalytic domain of human MMP-9 and co-crystallized it with active site-directed synthetic inhibitors of different binding types. Here, we present the X-ray structures of five MMP-9 complexes with gelatinase-specific, tight binding inhibitors: a phosphinic acid (AM-409), a pyrimidine-2,4,6-trione (RO-206-0222), two carboxylate (An-1 and MJ-24), and a trifluoromethyl hydroxamic acid inhibitor (MS-560). These compounds bind by making a compromise between optimal coordination of the catalytic zinc, favourable hydrogen bond formation in the active-site cleft, and accommodation of their large hydrophobic P1' groups in the slightly flexible S1' cavity, which exhibits distinct rotational conformations of the Pro421 carbonyl group in each complex. In all these structures, the side-chain of Arg424 located at the bottom of the S1' cavity is not defined in the electron density beyond C(gamma), indicating its mobility. However, we suggest that the mobile Arg424 side-chain partially blocks the S1' cavity, which might explain the weaker binding of most inhibitors with a long P1' side-chain for MMP-9 compared with the closely related MMP-2 (gelatinase A), which exhibits a short threonine side-chain at the equivalent position. These novel structural details should facilitate the design of more selective MMP-9 inhibitors.

PubMed: 17599356
DOI: 10.1016/j.jmb.2007.05.068

Experimental method

X-RAY DIFFRACTION (2.9 Å)