7XJO
Crystal structure of human MMP-2 catalytic domain in complex with inhibitor
Summary for 7XJO
| Entry DOI | 10.2210/pdb7xjo/pdb |
| Descriptor | Matrix metalloproteinase-2, RYH-KFB-GLU-ASP-DAB-LEU-EME-EOE-NH2, ZINC ION, ... (7 entities in total) |
| Functional Keywords | gelatinase a, matrix metalloproteinase-2, 72 kda type iv collagenase, hydrolase |
| Biological source | Homo sapiens More |
| Total number of polymer chains | 4 |
| Total formula weight | 40682.94 |
| Authors | Kamitani, M.,Mima, M.,Takeuchi, T. (deposition date: 2022-04-18, release date: 2022-06-29, Last modification date: 2023-11-29) |
| Primary citation | Takeuchi, T.,Hayashi, M.,Tamita, T.,Nomura, Y.,Kojima, N.,Mitani, A.,Takeda, T.,Hitaka, K.,Kato, Y.,Kamitani, M.,Mima, M.,Toki, H.,Ohkubo, M.,Nozoe, A.,Kakinuma, H. Discovery of Aryloxyphenyl-Heptapeptide Hybrids as Potent and Selective Matrix Metalloproteinase-2 Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis. J.Med.Chem., 65:8493-8510, 2022 Cited by PubMed Abstract: Matrix metalloproteinase-2 (MMP2) is a zinc-dependent endopeptidase that plays important roles in the degradation of extracellular matrix proteins. MMP2 is considered to be an attractive target for the treatment of various diseases such as cancer, arthritis, and fibrosis. In this study, we have developed a novel class of MMP2-selective inhibitors by hybridizing the peptide that binds to a zinc ion and S2-S5 pockets with small molecules that bind to the S1' pocket. Structural modifications based on X-ray crystallography revealed that the introduction of 2,4-diaminobutanoic acid (Dab) at position 4 dramatically enhanced MMP2 selectivity by forming an electrostatic interaction with Glu130. After improving the metabolic and chemical stability, TP0556351 () was identified. It exhibited potent MMP2 inhibitory activity (IC = 0.20 nM) and extremely high selectivity. It suppressed the accumulation of collagen in a bleomycin-induced idiopathic pulmonary fibrosis model in mice, demonstrating the efficacy of MMP2-selective inhibitors for fibrosis. PubMed: 35687819DOI: 10.1021/acs.jmedchem.2c00613 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
Download full validation report
