title: Homology modeling of a Class A GPCR in the inactive conformation: A quantitative analysis of the correlation between model/template sequence identity and model accuracy.
abstract: With the present work we quantitatively studied the modellability of the inactive state of Class A G protein-coupled receptors (GPCRs). Specifically, we constructed models of one of the Class A GPCRs for which structures solved in the inactive state are available, namely the β2AR, using as templates each of the other class members for which structures solved in the inactive state are also available. Our results showed a detectable linear correlation between model accuracy and model/template sequence identity. This suggests that the likely accuracy of the homology models that can be built for a given receptor can be generally forecasted on the basis of the available templates. We also probed whether sequence alignments that allow for the presence of gaps within the transmembrane domains to account for structural irregularities afford better models than the classical alignment procedures that do not allow for the presence of gaps within such domains. As our results indicated, although the overall differences are very subtle, the inclusion of internal gaps within the transmembrane domains has a noticeable a beneficial effect on the local structural accuracy of the domain in question.
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA; Center for Behavioral Neuroscience, American University, Washington, DC 20016, USA. Electronic address: costanzi@american.edu.
authors.forename: Stefano
authors.initials: S
authors.lastname: Costanzi
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Skorski
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Deplano
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Habermehl
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Mendoza
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Keyun
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Biederman
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Department of Chemistry, American University, Washington, DC 20016, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Gao
mesh_terms: D000595:Amino Acid Sequence; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D043562:Receptors, G-Protein-Coupled
keywords: G protein-coupled receptors; GPCRs; Homology modeling; Sequence alignment; β(2) adrenergic receptor