Structural bioinformatics analysis of variants on GPCR function.

Structural bioinformatics analysis of variants on GPCR function.

Publication date: Jun 04, 2019

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.

Syed Haneef, S.A. and Ranganathan, S. Structural bioinformatics analysis of variants on GPCR function. 04756. 2019 Curr Opin Struct Biol (55):

Concepts Keywords
Binding Site Endocannabinoid system
Cannabinoid Receptor CB1 G protein-coupled receptors
CB1 Cell biology
Central Nervous System Branches of biology
Drug Target
Endocannabinoid System
G Protein
GPCR
Ligand
Membrane
Molecular Dynamics
Mutants
Pain
Pharmacogenomics
Phenotypic
Precision Medicine
Protein
Receptor
Receptors
Signal Transduction
Single Nucleotide Polymorphisms
X Ray

Semantics

Type Source Name
gene UNIPROT SH3YL1
gene UNIPROT RAB35
gene UNIPROT THOP1
gene UNIPROT SGSM3
gene UNIPROT CNR1
gene UNIPROT ERAL1
gene UNIPROT ESR1
pathway BSID Signal Transduction
gene UNIPROT FZD4
gene UNIPROT MRGPRX3
gene UNIPROT LPAR3
gene UNIPROT GPR151
gene UNIPROT MRGPRX4
gene UNIPROT OXER1
gene UNIPROT GPRC6A
gene UNIPROT LGR6
gene UNIPROT MRGPRX1

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