Towards Improved Quality of GPCR Models by Usage of Multiple Templates and Profile-Profile Comparison

Abstract

G-protein coupled receptors (GPCRs) are targets of nearly one third of the drugs at the current pharmaceutical market. Despite their importance in many cellular processes the crystal structures are available for less than 20 unique GPCRs of the Rhodopsin-like class. Fortunately, even though involved in different signaling cascades, this large group of membrane proteins has preserved a uniform structure comprising seven transmembrane helices that allows quite reliable comparative modeling. Nevertheless, low sequence similarity between the GPCR family members is still a serious obstacle not only in template selection but also in providing theoretical models of acceptable quality. An additional level of difficulty is the prediction of kinks and bulges in transmembrane helices. Usage of multiple templates and generation of alignments based on sequence profiles may increase the rate of success in difficult cases of comparative modeling in which the sequence similarity between GPCRs is exceptionally low. Here, we present GPCRM, a novel method for fast and accurate generation of GPCR models using averaging of multiple template structures and profile-profile comparison. In particular, GPCRM is the first GPCR structure predictor incorporating two distinct loop modeling techniques: Modeller and Rosetta together with the filtering of models based on the Z-coordinate. We tested our approach on all unique GPCR structures determined to date and report its performance in comparison with other computational methods targeting the Rhodopsin-like class. We also provide a database of precomputed GPCR models of the human receptors from that class.AvailabilityGPCRM server and database: http://gpcrm.biomodellab.eu

Detection of New Biased Agonists for the Serotonin 5-HT2A Receptor: Modeling and Experimental Validation

“…The modeling protocol included alignment of the sequence of the serotonin 5-HT 2A receptor to the one on the b2-adrenergic receptor in complex with G s (PBD ID 3SN6) using Molecular Operating Environment (MOE) software (http://www.chemcomp.com/software.htm). A structural model of the receptor was then built using MODELER software (Latek et al, 2013). The resulting structures were optimized using the AMBER12: extended Hueckel theory force field (Case, 2012) in the MOE software.…”

GPCRdb: the G protein‐coupled receptor database – an introduction

“…Finally, specialized web servers exist for GPCR homology modelling; GPCRM (Latek et al, ), GoMoDo (Sandal et al, ) and SSFE (Worth et al, ); and molecular dynamics: GPCR Mod‐Sim (Rodríguez et al, ). The GPCRdb is working together with these servers towards exchange of resources and competences.…”

Identifying ligands at orphan GPCRs: current status using structure‐based approaches

“…Critically, five novel ligands were identified by screening against this mixed‐template homology model of GPR17 (100% hit rate in validation assays) (Eberini et al, ). The use of chimeric templates is not unprecedented; it has been shown previously that matching TMs to individual templates improved the RMSD of the binding site area of models to their reference crystal structure (Worth et al, ; Latek et al, ). However, other evaluation metrics were not considered, such as ligand–receptor contact‐based methods (Kufareva and Abagyan, ).…”