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

H. E. Xu, M. H. Lambert, V. G. Montana, K. D. Plunket, L. B. Moore, J. L. Collins, J. A. Oplinger, S. A. Kliewer, Jr Gampe R.T., D. D. McKee, J. T. Moore, T. M. Willson

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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.

Original languageEnglish (US)
Pages (from-to)13919-13924
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number24
DOIs
StatePublished - Nov 20 2001

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    Xu, H. E., Lambert, M. H., Montana, V. G., Plunket, K. D., Moore, L. B., Collins, J. L., Oplinger, J. A., Kliewer, S. A., Gampe R.T., J., McKee, D. D., Moore, J. T., & Willson, T. M. (2001). Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences of the United States of America, 98(24), 13919-13924. https://doi.org/10.1073/pnas.241410198