NDLI: Structural Basis for Matrix Metalloproteinase-2 (MMP-2)-selective Inhibitory Action of β-Amyloid Precursor Protein-derived Inhibitor*

Content Provider	PubMed Central
Author	Hashimoto, Hiroshi Takeuchi, Tomoka Komatsu, Kyoko Miyazaki, Kaoru Sato, Mamoru Higashi, Shouichi
Copyright Year	2011
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 Tyr3 of the inhibitor is accommodated into the S1′ pocket of the protease, and the carboxylate group of Asp6 of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala7 to Pro10 and Tyr3 to Ile1 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.
Related Links	http://dx.doi.org/10.1074/jbc.m111.264176
Ending Page	33243
Page Count	8
Starting Page	33236
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	38
Volume Number	286
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2011-09-23
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Structural Basis for Matrix Metalloproteinase-2 (MMP-2)-selective Inhibitory Action of β-Amyloid Precursor Protein-derived Inhibitor

Molecular Design of a Highly Selective and Strong Protein Inhibitor against Matrix Metalloproteinase-2 (MMP-2)

Identification of Amino Acid Residues of the Matrix Metalloproteinase-2 Essential for Its Selective Inhibition by β-Amyloid Precursor Protein-derived Inhibitor

Identification of a Region of β-Amyloid Precursor Protein Essential for Its Gelatinase A Inhibitory Activity

Molecular Design of a Highly Selective and Strong Protein Inhibitor against Matrix Metalloproteinase-2 (MMP-2)*

Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient Mice

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Sequential Amyloid-β Degradation by the Matrix Metalloproteases MMP-2 and MMP-9

Structural Basis for Matrix Metalloproteinase-2 (MMP-2)-selective Inhibitory Action of β-Amyloid Precursor Protein-derived Inhibitor*

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