7OPN
Human Aldehyde Oxidase SNP R1231H in complex with Raloxifene
Summary for 7OPN
| Entry DOI | 10.2210/pdb7opn/pdb |
| Related | 7ORC |
| Descriptor | Aldehyde oxidase, DIMETHYL SULFOXIDE, FE2/S2 (INORGANIC) CLUSTER, ... (11 entities in total) |
| Functional Keywords | human aldehyde oxidase, single nucleotide polymorphism, complex, inhibitor, oxidoreductase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 302261.18 |
| Authors | Mota, C.,Coelho, C.,Santos Silva, T.,Romao, M.J. (deposition date: 2021-06-01, release date: 2021-09-01, Last modification date: 2024-01-31) |
| Primary citation | Mota, C.,Diniz, A.,Coelho, C.,Santos-Silva, T.,Esmaeeli, M.,Leimkuhler, S.,Cabrita, E.J.,Marcelo, F.,Romao, M.J. Interrogating the Inhibition Mechanisms of Human Aldehyde Oxidase by X-ray Crystallography and NMR Spectroscopy: The Raloxifene Case. J.Med.Chem., 64:13025-13037, 2021 Cited by PubMed Abstract: Human aldehyde oxidase (hAOX1) is mainly present in the liver and has an emerging role in drug metabolism, since it accepts a wide range of molecules as substrates and inhibitors. Herein, we employed an integrative approach by combining NMR, X-ray crystallography, and enzyme inhibition kinetics to understand the inhibition modes of three hAOX1 inhibitors-thioridazine, benzamidine, and raloxifene. These integrative data indicate that thioridazine is a noncompetitive inhibitor, while benzamidine presents a mixed type of inhibition. Additionally, we describe the first crystal structure of hAOX1 in complex with raloxifene. Raloxifene binds tightly at the entrance of the substrate tunnel, stabilizing the flexible entrance gates and elucidating an unusual substrate-dependent mechanism of inhibition with potential impact on drug-drug interactions. This study can be considered as a proof-of-concept for an efficient experimental screening of prospective substrates and inhibitors of hAOX1 relevant in drug discovery. PubMed: 34415167DOI: 10.1021/acs.jmedchem.1c01125 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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