9MS2
Crystal structure of human CYP3A5 in complex with SJYHJ-111
This is a non-PDB format compatible entry.
Summary for 9MS2
| Entry DOI | 10.2210/pdb9ms2/pdb |
| Related | 9BV9 |
| Descriptor | Cytochrome P450 3A5, PROTOPORPHYRIN IX CONTAINING FE, N'-(2-chlorophenyl)-N-[(3-hydroxyphenyl)methyl]-N-[(2P)-2-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]urea, ... (7 entities in total) |
| Functional Keywords | cytochrome p450 3a5, cyp3a5, cyp3a5-selective inhibitor, drug metabolizing enzyme, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 112948.98 |
| Authors | Jingheng, W.,Nithianantham, S.,Miller, D.J.,Chen, T. (deposition date: 2025-01-09, release date: 2025-04-16, Last modification date: 2025-04-23) |
| Primary citation | Wang, J.,Nithianantham, S.,Chai, S.C.,Jung, Y.H.,Yang, L.,Ong, H.W.,Li, Y.,Zhang, Y.,Miller, D.J.,Chen, T. Decoding the selective chemical modulation of CYP3A4. Nat Commun, 16:3423-3423, 2025 Cited by PubMed Abstract: Drug-drug interactions associate with concurrent uses of multiple medications. Cytochrome P450 (CYP) 3A4 metabolizes a large portion of marketed drugs. To maintain the efficacy of drugs metabolized by CYP3A4, pan-CYP3A inhibitors such as ritonavir are often co-administered. Although selective CYP3A4 inhibitors have greater therapeutic benefits as they avoid inhibiting unintended CYPs and undesirable clinical consequences, the high homology between CYP3A4 and CYP3A5 has hampered the development of such selective inhibitors. Here, we report a series of selective CYP3A4 inhibitors with scaffolds identified by high-throughput screening. Structural, functional, and computational analyses reveal that the differential C-terminal loop conformations and two distinct ligand binding surfaces disfavor the binding of selective CYP3A4 inhibitors to CYP3A5. Structure-guided design of compounds validates the model and yields analogs that are selective for CYP3A4 versus other major CYPs. These findings demonstrate the feasibility to selectively inhibit CYP3A4 and provide guidance for designing better CYP3A4 selective inhibitors. PubMed: 40210880DOI: 10.1038/s41467-025-58749-8 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.25 Å) |
Structure validation
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