Impact of Helix Irregularities on Sequence Alignment and Homology Modeling of G Protein‐Coupled Receptors

Abstract

Comparison of the crystal structures of G protein-coupled receptors (GPCRs) revealed backbone irregularities in the majority of the transmembrane (TM) helices. Among these, wide (π bulge) and tight (3(10)) helical turns on TM2 and TM5 deserve special attention because of their proximity to the ligand binding site. These irregularities are related to residue insertion or deletion (reflected by inclusion of gaps in sequence alignments) accumulated during the evolution of these two helices. These findings have direct implications for the sequence alignments, phylogeny reconstruction, and homology modeling of class A GPCRs.

Structural Determinants for the Interaction of Formyl Peptide Receptor 2 with Peptide Ligands

“…It can be seen that FPRs are located in a branch that includes opioid receptors (OPRX, OPRK, OPRD, and OPRM), the protease-activated receptor (PAR1), the neurotensin receptor (NTR1), and the chemokine CXCR4 and CCR5 receptors, with the latter being the most closely related receptor. This subfamily of peptide receptors is characterized by unique molecular signatures such as an ECL2 formed by two ␤-strands that maintain the binding site accessible from the extracellular environment and a closed helical segment (310 helix or tight turn) at the extracellular part of TM2 due to the conserved (S/T)ϫP2.58 motif (16). Thus, FPR1 and FPR2 were modeled using the structure of the CXCR4 chemokine receptor as template (PDB code 3ODU) (17) using Modeler 9v8 (18 (19), were used as reference points in TM sequence alignments (see Fig.…”

Structure Prediction of Transmembrane Proteins

“…Predicting TMP structures, at first, seems to be a relatively easy problem compared to understanding soluble protein structures. The fact that many TMPs share similar folds even with marginal sequence identities [43,129] proves that TMPs are more structurally conserved than globular proteins. This is due to the strict conformational constraints that come from the membrane lipid bilayer, which dramatically decreases the size of the conformational space.…”

“…There are some examples for modeling GPCR receptors [4,43], but there isn't any fully automated, membrane protein specific method. Other, non-specific methods [122] are used as well, but the constraints imposed by the membrane are not utilized in the modeling, and the applied scoring functions designed for globular proteins might lead to distorted models.…”

N‐Alkylacylamides in Thin Films Display Infrared Spectra of 310‐, α‐, and π‐Helices with Visible Static and Dynamic Growth Phases

“…[20] Analyses of structures have made clear the role of p-bulges in various proteins. [21][22][23] As a continuation of our previous work on NMF, we decided to look for the presence of the a-helix found by Neuefeind. [24] We discovered that, at a signal strength of 1000 (still well below the Sg 10 000 of a typical IR source), clear peaks could be observed.…”