Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.
LanguageEnglish
Title of host publicationApplication of GPCR Structures for Modelling of Free Fatty Acid Receptors
PublisherSpringer
Publication statusAccepted - 04 Oct 2016

Publication series

NameHandbook of Experimental Pharmacology
PublisherSpringer
ISSN (Electronic)0171-2004

Fingerprint

G-Protein-Coupled Receptors
Nonesterified Fatty Acids
Arginine
Fatty Acids
Mutagenesis
Crystallography
Volatile Fatty Acids
Medical problems
Modulators
Crystal structure
Modulation
Ligands
Molecules

Cite this

Tikhonova, I. G. (Accepted/In press). Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. In Application of GPCR Structures for Modelling of Free Fatty Acid Receptors (Handbook of Experimental Pharmacology). Springer.
Tikhonova, Irina G. / Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. Springer, 2016. (Handbook of Experimental Pharmacology).
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Tikhonova, IG 2016, Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. in Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. Handbook of Experimental Pharmacology, Springer.

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. / Tikhonova, Irina G.

Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. Springer, 2016. (Handbook of Experimental Pharmacology).

Research output: Chapter in Book/Report/Conference proceedingChapter

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T1 - Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

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AB - Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors. Analysis of the crystal structure and improved homology models, along with mutagenesis data and structure activity, highlighted an unusual arginine charge pairing interaction in FFA1-3 for receptor modulation, distinct structural features for ligand binding to FFA1 and FFA4 and an arginine of the second extracellular loop as a possible anchoring point for FFA at GPR84. Structural data will be helpful for searching novel small molecule modulators at the FFA receptors.

M3 - Chapter

T3 - Handbook of Experimental Pharmacology

BT - Application of GPCR Structures for Modelling of Free Fatty Acid Receptors

PB - Springer

ER -

Tikhonova IG. Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. In Application of GPCR Structures for Modelling of Free Fatty Acid Receptors. Springer. 2016. (Handbook of Experimental Pharmacology).