Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

doi:10.1073/pnas.241410198

Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709

Edited by Michael G. Rosenfeld, University of California at San Diego, La Jolla, CA, and approved September 27, 2001 (received for review August 3, 2001)

Abstract

The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPARα and histidine in PPARγ, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases.

Footnotes

↵ * To whom correspondence on the structure determination and requests for materials should be addressed. E-mail: ex11957{at}gsk.com.
↵ † To whom correspondence on molecular modeling should be addresssed. E-mail: mhl8097{at}gsk.com.
↵ ‡ To whom additional correspondence and reprint requests should be addressed. E-mail: tmw20653{at}gsk.com.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.rcsb.org (PDB ID codes 1K7L and 1K74).
Abbreviations:

PPAR,

peroxisome proliferator-activated receptor;

TZD,

thiazolidinedione;

LBD,

ligand binding domain;

FA,

fatty acid;

SRC1,

steroid receptor coactivator 1