PDBsum entry 6lx7

Transcription

PDB id: 6lx7

Contents

Protein chain

268 a.a.

Ligands

GOL

STE

Waters ×201

PDB id:

6lx7

Name:

Transcription

Title:

X-ray structure of human pparalpha ligand binding domain-stearic acid co-crystals obtained by delipidation and cross-seeding

Structure:

Peroxisome proliferator-activated receptor alpha. Chain: a. Engineered: yes

Source:

Homo sapiens. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.41Å R-factor: 0.176 R-free: 0.192

Authors:

S.Kamata,K.Saito,A.Honda,R.Ishikawa,T.Oyama,I.Ishii

Key ref:

S.Kamata et al. (2020). PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates. iScience, 23, 101727. PubMed id: 33205029 DOI: 10.1016/j.isci.2020.101727

Date:

10-Feb-20 Release date: 11-Nov-20

Protein chain

Q07869  (PPARA_HUMAN) -  Peroxisome proliferator-activated receptor alpha from Homo sapiens

Seq: 468 a.a.

Struc: 268 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.isci.2020.101727

iScience 23:101727 (2020)

PubMed id: 33205029

PPARα Ligand-Binding Domain Structures with Endogenous Fatty Acids and Fibrates.

S.Kamata, T.Oyama, K.Saito, A.Honda, Y.Yamamoto, K.Suda, R.Ishikawa, T.Itoh, Y.Watanabe, T.Shibata, K.Uchida, M.Suematsu, I.Ishii.

ABSTRACT

Most triacylglycerol-lowering fibrates have been developed in the 1960s-1980s before their molecular target, peroxisome proliferator-activated receptor alpha (PPARα), was identified. Twenty-one ligand-bound PPARα structures have been deposited in the Protein Data Bank since 2001; however, binding modes of fibrates and physiological ligands remain unknown. Here we show thirty-four X-ray crystallographic structures of the PPARα ligand-binding domain, which are composed of a "Center" and four "Arm" regions, in complexes with five endogenous fatty acids, six fibrates in clinical use, and six synthetic PPARα agonists. High-resolution structural analyses, in combination with coactivator recruitment and thermostability assays, demonstrate that stearic and palmitic acids are presumably physiological ligands; coordination to Arm III is important for high PPARα potency/selectivity of pemafibrate and GW7647; and agonistic activities of four fibrates are enhanced by the partial agonist GW9662. These results renew our understanding of PPARα ligand recognition and contribute to the molecular design of next-generation PPAR-targeted drugs.