Structural bioinformatics analysis of variants on GPCR function

Research output: Contribution to journalReview articleResearchpeer-review

Abstract

G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.

LanguageEnglish
Pages161-177
Number of pages17
JournalCurrent Opinion in Structural Biology
Volume55
DOIs
Publication statusPublished - Apr 2019

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Cannabinoid Receptors
G-Protein-Coupled Receptors
Computational Biology
Endocannabinoids
Precision Medicine
Mutation
Pharmacogenetics
Disease Susceptibility
Molecular Dynamics Simulation
GTP-Binding Proteins
Protein Binding
Pharmaceutical Preparations
Single Nucleotide Polymorphism
Signal Transduction
Central Nervous System
Binding Sites
X-Rays
Ligands
Pain
Membranes

Cite this

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title = "Structural bioinformatics analysis of variants on GPCR function",
abstract = "G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.",
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Structural bioinformatics analysis of variants on GPCR function. / Syed Haneef, Syed Askar; Ranganathan, Shoba.

In: Current Opinion in Structural Biology, Vol. 55, 04.2019, p. 161-177.

Research output: Contribution to journalReview articleResearchpeer-review

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