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

Research output: Contribution to journalArticle

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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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Peroxisome Proliferator-Activated Receptors
Ligands
Nuclear Receptor Coactivator 1
Drug Design
Metabolic Diseases
Lipid Metabolism
Histidine
Tyrosine
Cardiovascular Diseases
Cholesterol
X-Rays
Amino Acids
Glucose

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. / 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., Jr; McKee, D. D.; Moore, J. T.; Willson, T. M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 24, 20.11.2001, p. 13919-13924.

Research output: Contribution to journalArticle

Xu, HE, Lambert, MH, Montana, VG, Plunket, KD, Moore, LB, Collins, JL, Oplinger, JA, Kliewer, SA, Gampe R.T., J, McKee, DD, Moore, JT & Willson, TM 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, vol. 98, no. 24, pp. 13919-13924. https://doi.org/10.1073/pnas.241410198
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., Jr ; McKee, D. D. ; Moore, J. T. ; Willson, T. M. / Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 24. pp. 13919-13924.
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