6HL1

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

Replaces:  4QE6

Summary for 6HL1

• Entry DOI: 10.2210/pdb6hl1/pdb
• Descriptor: Bile acid receptor, NCoA-2 peptide (Nuclear receptor coactivator 2), LYS-GLU-ASN-ALA-LEU-LEU-ARG-TYR-LEU-LEU-ASP-LYS-ASP, CHENODEOXYCHOLIC ACID, ... (4 entities in total)
• Functional Keywords: activator, dna-binding, receptor, repressor, complex, nuclear protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 29145.63

Authors

Kudlinzki, D.,Merk, D.,Linhard, V.L.,Saxena, K.,Schubert-Zsilavecz, M.,Schwalbe, H. (deposition date: 2018-09-10, release date: 2019-05-29, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.599 Å)