Generic GPCR Residue Numbers - Aligning Topology Maps Minding The Gaps

By Vignir Ísberg, C. de Graaf, A. Bortolato, Vadim Cherezov, Vsevolod Katritch, F. Marshall, Stefan Mordalski, J. Pin, Raymond C. Stevens, G. Vriend and 1 more. 2014

453 citations recorded by the source corpus.

Generic residue numbers facilitate comparisons of e.g. mutational effects, ligand interactions, and structural motifs. The class A GPCR residue numbering by Ballesteros and Weinstein has more than 1100 citations, and the recent crystal structures for class B, C and F now call for community consensus in residue numbering within and across these classes. Furthermore, the structural era has uncovered helix bulges and constrictions that offset the generic residue numbers. The use of generic residue numbers depends on convenient access by pharmacologists, chemists and structural biologists. We review the generic residue numbering schemes for each GPCR class, as well as a complementary structure-based scheme, provide illustrative case stories and GPCRDB web tools to number any receptor sequence or structure.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

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Citations in the corpus

GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, methodology): “Generic residue numbers allow different receptors to be compared at the residue-level by assigning a common index for the receptor segment (TM1–7, H8 or ICL/ECL1–2) and a position therein that is equivalent in sequence or, in the case of GPCRdb numbering, in structure (see Materials and Methods and ”
Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs (2020, background): “As more receptor structures became available, it was found that not all receptor families adhere strictly to the i to i+4 periodicity in every α-helix [34].”
An Online Resource for GPCR Structure Determination and Analysis (2019, methodology): “38 and Supplementary Note).”
Integrating structural and mutagenesis data to elucidate GPCR ligand binding (2016, methodology): “GPCRdb uses a structure-based residue numbering based on Ballesteros–Weinstein numbers, but adjusting numbers and sequence alignments to account helix bulges and constrictions [39].”
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors (2019, methodology): “, 2018) including structurebased GPCRdb numbering as an adaption of the sequence-based Ballesteros-Weinstein scheme with corrections for helix bulges and constrictions (Isberg et al., 2015).”
GPCRdb: an information system for G protein-coupled receptors (2015, background): “GPCRdb is the first to offer structure-based GPCR sequence alignments and generic residue numbers (24).”
GPCR-SSFE 2.0—a fragment-based molecular modeling web tool for Class A G-protein coupled receptors (2017, background): “A distinct feature of TSHR compared to other Class A GPCRs is that in TMH5 it lacks the highly conserved proline in position 5×50 (modified Ballesteros–Weinstein nomenclature that considers the structural alignment of bulges (33)) instead having an alanine (Ala593) at this position.”
GPCRdb in 2018: adding GPCR structure models and ligands (2017, background): “It leverages on integration of several unique manually annotated GPCRdb resources, including structure-based sequence alignments with generic residue numbers (16), GPCR structures (all in PDB) with defined preferred chain, helix segment borders, and distorted regions; and a position-specific sidecha”
Structure of the class D GPCR Ste2 dimer coupled to two G proteins (2020, unknown): “Consistent with the generic residue numbering schemes of other GPCR classes 72 , the most conserved residue in each predicted transmembrane helix was identified and annotated as the numbering reference position with the number 50.”
A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, background): “proposed in the literature to facilitate the identification of corresponding residues using generic residue numbers [46].”
AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors (2022, background): “According to the traditional classification of GPCRs, these 29 structures are categorized in classes A, B1, and F [18, 19].”
GPCRdb: the G protein‐coupled receptor database – an introduction (2016, methodology): “Furthermore, the alignments are assigned a single-residue gap where a helix bulge or constriction has caused a gap in the structure, as described under generic residue numbers below (Isberg et al., 2015).”