GPCRM: a homology modeling web service with triple membrane-fitted quality assessment of GPCR models

Abstract

Due to the involvement of G protein-coupled receptors (GPCRs) in most of the physiological and pathological processes in humans they have been attracting a lot of attention from pharmaceutical industry as well as from scientific community. Therefore, the need for new, high quality structures of GPCRs is enormous. The updated homology modeling service GPCRM (http://gpcrm.biomodellab.eu/) meets those expectations by greatly reducing the execution time of submissions (from days to hours/minutes) with nearly the same average quality of obtained models. Additionally, due to three different scoring functions (Rosetta, Rosetta-MP, BCL::Score) it is possible to select accurate models for the required purposes: the structure of the binding site, the transmembrane domain or the overall shape of the receptor. Currently, no other web service for GPCR modeling provides this possibility. GPCRM is continually upgraded in a semi-automatic way and the number of template structures has increased from 20 in 2013 to over 90 including structures the same receptor with different ligands which can influence the structure not only in the on/off manner. Two types of protein viewers can be used for visual inspection of obtained models. The extended sortable tables with available templates provide links to external databases and display ligand–receptor interactions in visual form.

A free‐energy landscape for the glucagon‐like peptide 1 receptor GLP1R

“…In trying to generalize a perspective about the outcome of this work to GPCRs as a family, it is worth nothing that the mechanism of GPCRs as a whole is probably shared between most members of the family, and the details of the interactions with partners and subsequent effects on them and cascading cellular response, is probably common between all members that bind the same cognate G protein (eg, G s ). The common mechanism assumption is probably best supported by GPCR architecture being well preserved (even in cases of low sequence similarity) and the common binding pocket for G protein partners, on the cytoplasmic face of different receptors, and shows that our results could serve as a cornerstone in further understanding of GLP1R, or other GPCRs as well.…”

Hybrid MM/CG Webserver: Automatic Set Up of Molecular Mechanics/Coarse-Grained Simulations for Human G Protein-Coupled Receptor/Ligand Complexes

“…The input PDB file can be obtained from experimental databases, such as the Protein Data Bank ( Berman et al, 2000 ; Rose et al, 2016 ), GPCRdb ( Pándy-Szekeres et al, 2018 ) or GPCRmd ( Rodríguez-Espigares et al, 2020 ), as well as computational services like GOMoDo ( Sandal et al, 2013 ), GPCR-ModSim ( Esguerra et al, 2016 ), GPCR-SSFE ( Worth et al, 2017 ), GPCRM ( Miszta et al, 2018 ), Galaxy7TM ( Lee and Seok, 2016 ), GPCRautomodel ( Launay et al, 2012 ), @TOME ( Pons and Labesse, 2009 ) and others (reviewed in Busato and Giorgetti, 2016 ). The GOMoDo webserver ( Sandal et al, 2013 ), which can be used for homology modeling of hGPCRs and subsequent docking of ligands, is linked directly with the Hybrid MM/CG webserver.…”

Understanding Ligand Binding to G-Protein Coupled Receptors Using Multiscale Simulations

“…Given the lack of experimental structures, the initial structures of the receptor/ligand complexes are generated using bioinformatics approaches. Although there are several webservers specialized in GPCR modeling (Launay et al, 2012; Zhang et al, 2015; Busato and Giorgetti, 2016; Esguerra et al, 2016; Pándy-Szekeres et al, 2017; Worth et al, 2017; Miszta et al, 2018), here we used the GOMoDo webserver (Sandal et al, 2013), which combines in a single pipeline homology modeling and molecular docking for GPCRs.…”