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

doi:10.1073/pnas.241410198

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 journal › Article › peer-review

480 Scopus citations

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 language	English (US)
Pages (from-to)	13919-13924
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	98
Issue number	24
DOIs	https://doi.org/10.1073/pnas.241410198
State	Published - Nov 20 2001

ASJC Scopus subject areas

General

Access to Document

10.1073/pnas.241410198

Cite this

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

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

@article{dd43ae599e4742baa2f5c2cea2273ce6,

title = "Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors",

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.",

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

year = "2001",

month = nov,

day = "20",

doi = "10.1073/pnas.241410198",

language = "English (US)",

volume = "98",

pages = "13919--13924",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "24",

}

TY - JOUR

T1 - Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

AU - Xu, H. E.

AU - Lambert, M. H.

AU - Montana, V. G.

AU - Plunket, K. D.

AU - Moore, L. B.

AU - Collins, J. L.

AU - Oplinger, J. A.

AU - Kliewer, S. A.

AU - Gampe R.T., Jr

AU - McKee, D. D.

AU - Moore, J. T.

AU - Willson, T. M.

PY - 2001/11/20

Y1 - 2001/11/20

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0035923672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035923672&partnerID=8YFLogxK

U2 - 10.1073/pnas.241410198

DO - 10.1073/pnas.241410198

M3 - Article

C2 - 11698662

AN - SCOPUS:0035923672

SN - 0027-8424

VL - 98

SP - 13919

EP - 13924

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 24

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this