5IAW

Novel natural FXR modulator with a unique binding mode

Summary for 5IAW

• Entry DOI: 10.2210/pdb5iaw/pdb
• Descriptor: Bile acid receptor, Peptide from Nuclear receptor coactivator 2, (1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl 4-hydroxybenzoate, ... (4 entities in total)
• Functional Keywords: nuclear protein receptor, transcription
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus . Isoform 1: Nucleus . Isoform 2: Nucleus . Isoform 3: Nucleus . Isoform 4: Nucleus : Q96RI1
• Total number of polymer chains: 4
• Total formula weight: 56611.34

Authors

Lu, Y.,Li, Y. (deposition date: 2016-02-22, release date: 2017-03-08, Last modification date: 2024-03-20)

Primary citation

Zheng, W.,Lu, Y.,Lin, S.,Wang, R.,Qiu, L.,Zhu, Y.,Yao, B.,Guo, F.,Jin, S.,Jin, L.,Li, Y.
A Novel Class of Natural FXR Modulators with a Unique Mode of Selective Co-regulator Assembly
Chembiochem, 18:721-725, 2017

PubMed Abstract: The farnesoid X receptor (FXR) is an important target for drug discovery. Small molecules induce a conformational change in FXR that modulates its binding to co-regulators, thus resulting in distinct FXR functional profiles. However, the mechanisms for selectively recruiting co-regulators by FXR remain elusive, partly because of the lack of FXR-selective modulators. We report the identification of two natural terpenoids, tschimgine and feroline, as novel FXR modulators. Remarkably, their crystal structures uncovered a secondary binding pocket important for ligand binding. Further, tschimgine or feroline induced dynamic conformational changes in the activation function 2 (AF-2) surface, thus leading to differential co-regulator recruiting profiles, modulated by both hydrophobic and selective hydrogen-bond interactions unique to specific co-regulators. Our findings thus provide a novel structure template for optimization for FXR-selective modulators of clinical value.

PubMed: 28186695
DOI: 10.1002/cbic.201700059

Experimental method

X-RAY DIFFRACTION (2.58 Å)