8H78
Crystal structure of human MMP-2 catalytic domain in complex with inhibitor
Summary for 8H78
| Entry DOI | 10.2210/pdb8h78/pdb |
| Descriptor | Matrix metalloproteinase-2, ZINC ION, CALCIUM ION, ... (6 entities in total) |
| Functional Keywords | gelatinase a, matrix metalloproteinase-2, 72 kda type iv collagenase, hydrolase |
| Biological source | Homo sapiens |
| Total number of polymer chains | 2 |
| Total formula weight | 40050.90 |
| Authors | Kamitani, M.,Takeuchi, T.,Mima, M. (deposition date: 2022-10-19, release date: 2023-01-18, Last modification date: 2023-11-29) |
| Primary citation | Takeuchi, T.,Nomura, Y.,Tamita, T.,Nishikawa, R.,Kakinuma, H.,Kojima, N.,Hitaka, K.,Tamura, Y.,Kamitani, M.,Mima, M.,Nozoe, A.,Hayashi, M. Discovery of TP0597850: A Selective, Chemically Stable, and Slow Tight-Binding Matrix Metalloproteinase-2 Inhibitor with a Phenylbenzamide-Pentapeptide Hybrid Scaffold. J.Med.Chem., 66:822-836, 2023 Cited by PubMed Abstract: Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase and a promising target for various diseases, including cancer and fibrosis. Herein, we report the discovery of a novel MMP2-selective inhibitor with high chemical stability and slow tight-binding features. Based on the degradation mechanism of our small-molecule-peptide hybrid , the tripeptide linker {5-aminopentanoic acid [Ape(5)]-Glu-Asp} of was replaced by a shorter linker (γ-D-Glu). Phenylbenzamide was suitable for the new generation of MMP2 inhibitors as an S1' pocket-binding group. The introduction of (4)-aminoproline dramatically increased the chemical stability while maintaining high subtype selectivity because of its interaction with Glu130. TP0597850 () exhibited high stability over a wide range of pH values as well as potent MMP2 inhibition ( = 0.034 nM) and ≥2000-fold selectivity determined using the inhibition constants. A kinetic analysis revealed that it possesses slow tight-binding nature with a long MMP2 dissociative half-life ( = 265 min). PubMed: 36595440DOI: 10.1021/acs.jmedchem.2c01698 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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