8SVX
Crystal structure of the L428V mutant of pregnane X receptor ligand binding domain in complex with SJPYT-331
Summary for 8SVX
| Entry DOI | 10.2210/pdb8svx/pdb |
| Descriptor | Nuclear receptor subfamily 1 group I member 2, Nuclear receptor coactivator 1 fusion protein,Nuclear receptor coactivator 1, methyl 3-{[(1P)-1-(2,5-dimethoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carbonyl]amino}-4-{[(3S)-hexan-3-yl]oxy}benzoate, DIMETHYL SULFOXIDE, ... (4 entities in total) |
| Functional Keywords | pregnane x receptor (pxr), promiscuous ligand-activated protein, nuclear receptor subfamily 1, transcriptional regulator, drug metabolism, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 80834.45 |
| Authors | Garcia-Maldonado, E.,Huber, A.D.,Nithianantham, S.,Miller, D.J.,Chen, T. (deposition date: 2023-05-17, release date: 2024-05-15, Last modification date: 2024-06-05) |
| Primary citation | Garcia-Maldonado, E.,Huber, A.D.,Chai, S.C.,Nithianantham, S.,Li, Y.,Wu, J.,Poudel, S.,Miller, D.J.,Seetharaman, J.,Chen, T. Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR. Nat Commun, 15:4054-4054, 2024 Cited by PubMed Abstract: Nuclear receptors are ligand-activated transcription factors that can often be useful drug targets. Unfortunately, ligand promiscuity leads to two-thirds of receptors remaining clinically untargeted. PXR is a nuclear receptor that can be activated by diverse compounds to elevate metabolism, negatively impacting drug efficacy and safety. This presents a barrier to drug development because compounds designed to target other proteins must avoid PXR activation while retaining potency for the desired target. This problem could be avoided by using PXR antagonists, but these compounds are rare, and their molecular mechanisms remain unknown. Here, we report structurally related PXR-selective agonists and antagonists and their corresponding co-crystal structures to describe mechanisms of antagonism and selectivity. Structural and computational approaches show that antagonists induce PXR conformational changes incompatible with transcriptional coactivator recruitment. These results guide the design of compounds with predictable agonist/antagonist activities and bolster efforts to generate antagonists to prevent PXR activation interfering with other drugs. PubMed: 38744881DOI: 10.1038/s41467-024-48472-1 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.14 Å) |
Structure validation
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