6HL0

Crystal Structure of Farnesoid X receptor (FXR) with bound NCoA-2 peptide

6HL0 の概要

• エントリーDOI: 10.2210/pdb6hl0/pdb
• 分子名称: Bile acid receptor, NCoA-2 peptide (Nuclear receptor coactivator 2), LYS-GLU-ASN-ALA-LEU-LEU-ARG-TYR-LEU-LEU-ASP-LYS-ASP (3 entities in total)
• 機能のキーワード: activator, dna-binding, receptor, repressor, complex, nuclear protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28753.05

構造登録者

Kudlinzki, D.,Merk, D.,Linhard, V.L.,Saxena, K.,Schubert-Zsilavecz, M.,Schwalbe, H. (登録日: 2018-09-10, 公開日: 2019-05-29, 最終更新日: 2024-01-24)

主引用文献

Merk, D.,Sreeramulu, S.,Kudlinzki, D.,Saxena, K.,Linhard, V.,Gande, S.L.,Hiller, F.,Lamers, C.,Nilsson, E.,Aagaard, A.,Wissler, L.,Dekker, N.,Bamberg, K.,Schubert-Zsilavecz, M.,Schwalbe, H.
Molecular tuning of farnesoid X receptor partial agonism.
Nat Commun, 10:2915-2915, 2019

PubMed Abstract: The bile acid-sensing transcription factor farnesoid X receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an extended helix α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions helix α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in helix α11 that destabilizes the α11-α12 loop, a critical determinant for helix α12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.

PubMed: 31266946
DOI: 10.1038/s41467-019-10853-2

実験手法

X-RAY DIFFRACTION (1.66 Å)