Generic GPCR residue numbers – aligning topology maps while minding the gaps

Abstract

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.

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

“…Alternatively, the shorter ICL3_KGKY loop might pose constraints of proper folding of the receptor. Indeed, according to alignments at GPCRdb (34), all the 21 other human class C GPCRs have ICL3 loops 2-4 amino acids longer than the short (ICL3_KGKY) h6A variant. Interestingly, the closest homolog, human calcium-sensing receptor, shares the RKLP motif present in the long h6A (ICL3_KGRKLP) variant, and the RXXP motif is conserved in Shown is an alignment of the published, short ICL3_KGKY variant, as well as the three longer variants.…”

Functional elements of the gastric inhibitory polypeptide receptor: Comparison between secretin- and rhodopsin-like G protein-coupled receptors

“…The value 100 for expression of wild type GIPR determined by binding of DY647-GIP corresponded to a binding capacity (B max ) of 1.8 AE 0.4 pM/10 6 cells as determined by analysis of homologous binding using 125 I-Phe1-GIP (see Section 2). Residue numbers in superscripts indicate the sequence-based generic GPCR numbering schemes for classes A and B [54].…”

“…(B)Comparison of the amino acids forming the functional domains within secretin-like receptors. Numbers in superscript/subscript refer to the sequence-based generic GPCR residue numbering schemes for classes A and B, respectively[54]. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)…”

Smoothened Regulation: A Tale of Two Signals

“…The Hh pathway is controlled by two membrane proteins, Patched (Ptch), the Hh receptor, and Smoothened (Smo), a Class F G protein-coupled receptor (GPCR) which transduces the activation signal to downstream pathway components (Figure 1A and [4-7]). In the absence of Hh ligand, Ptch inhibits signaling by Smo.…”