3AYU

Crystal structure of MMP-2 active site mutant in complex with APP-drived decapeptide inhibitor

Summary for 3AYU

• Entry DOI: 10.2210/pdb3ayu/pdb
• Descriptor: 72 kDa type IV collagenase, Amyloid beta A4 protein, ZINC ION, ... (5 entities in total)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Secreted, extracellular space, extracellular matrix. Isoform 2: Cytoplasm: P08253; Membrane; Single-pass type I membrane protein: P05067
• Total number of polymer chains: 2
• Total formula weight: 20028.94

Authors

Hashimoto, H.,Takeuchi, T.,Komatsu, K.,Miyazaki, K.,Sato, M.,Higashi, S. (deposition date: 2011-05-17, release date: 2011-08-03, Last modification date: 2024-03-13)

Primary citation

Hashimoto, H.,Takeuchi, T.,Komatsu, K.,Miyazaki, K.,Sato, M.,Higashi, S.
Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of {beta}-amyloid precursor protein-derived inhibitor
J.Biol.Chem., 2011

PubMed Abstract: Unlike other synthetic or physiological inhibitors for matrix metalloproteinases (MMPs), the β-amyloid precursor protein-derived inhibitory peptide (APP-IP) having an ISYGNDALMP sequence has a high selectivity toward MMP-2. Our previous study identified amino acid residues of MMP-2 essential for its selective inhibition by APP-IP and demonstrated that the N to C direction of the decapeptide inhibitor relative to the substrate-binding cleft of MMP-2 is opposite that of substrate. However, detailed interactions between the two molecules remained to be clarified. Here, we determined the crystal structure of the catalytic domain of MMP-2 in complex with APP-IP. We found that APP-IP in the complex is indeed embedded into the substrate-binding cleft of the catalytic domain in the N to C direction opposite that of substrate. With the crystal structure, it was first clarified that the aromatic side chain of Tyr(3) of the inhibitor is accommodated into the S1' pocket of the protease, and the carboxylate group of Asp(6) of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala(7) to Pro(10) and Tyr(3) to Ile(1) strands of the inhibitor extend into the nonprime and the prime sides of the cleft, respectively. Therefore, the decapeptide inhibitor has long range contact with the substrate-binding cleft of the protease. This mode of interaction is probably essential for the high MMP-2 selectivity of the inhibitor because MMPs share a common architecture in the vicinity of the catalytic center, but whole structures of their substrate-binding clefts have sufficient variety for the inhibitor to distinguish MMP-2 from other MMPs.

PubMed: 21813640
DOI: 10.1074/jbc.M111.264176

Experimental method

X-RAY DIFFRACTION (2 Å)