8SZV

Crystal structure of pregnane X receptor ligand binding domain complexed with T0901317 analog SJPYT-318

Summary for 8SZV

• Entry DOI: 10.2210/pdb8szv/pdb
• Descriptor: Nuclear receptor subfamily 1 group I member 2, N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-N-[(4-phenoxyphenyl)methyl]benzenesulfonamide (3 entities in total)
• Functional Keywords: nuclear receptor, transcription factor, metabolism, antibiotic, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 36790.27

Authors

Huber, A.D.,Poudel, S.,Miller, D.J.,Li, Y.,Chen, T. (deposition date: 2023-05-30, release date: 2023-10-11, Last modification date: 2023-12-20)

Primary citation

Huber, A.D.,Poudel, S.,Li, Y.,Lin, W.,Wu, J.,Miller, D.J.,Chen, T.
Ligand flexibility and binding pocket malleability cooperate to allow selective PXR activation by analogs of a promiscuous nuclear receptor ligand.
Structure, 31:1545-, 2023

PubMed Abstract: The human nuclear receptor (NR) family of transcription factors contains 48 proteins that bind lipophilic molecules. Approved NR therapies have had immense success treating various diseases, but lack of selectivity has hindered efforts to therapeutically target the majority of NRs due to unpredictable off-target effects. The synthetic ligand T0901317 was originally discovered as a potent agonist of liver X receptors (LXRα/β) but subsequently found to target additional NRs, with activation of pregnane X receptor (PXR) being as potent as that of LXRs. We previously showed that directed rigidity reduces PXR binding by T0901317 derivatives through unfavorable protein remodeling. Here, we use a similar approach to achieve selectivity for PXR over other T0901317-targeted NRs. One molecule, SJPYT-318, accomplishes selectivity by favorably utilizing PXR's flexible binding pocket and surprisingly binding in a new mode distinct from the parental T0901317. Our work provides a structure-guided framework to achieve NR selectivity from promiscuous compounds.

PubMed: 37729916
DOI: 10.1016/j.str.2023.08.020

Experimental method

X-RAY DIFFRACTION (2.2 Å)