Selectivity determinants of GPCR-G-protein binding

TY - JOUR

T1 - Selectivity determinants of GPCR-G-protein binding

AU - Flock, Tilman

AU - Hauser, Alexander S

AU - Lund, Nadia

AU - Gloriam, David E

AU - Balaji, Santhanam

AU - Babu, M Madan

PY - 2017/5/18

Y1 - 2017/5/18

N2 - The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

AB - The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.

KW - Amino Acid Sequence

KW - GPCR

KW - Evolution, Molecular

KW - G-protein-coupled receptor

KW - G proteins

KW - Structural Homology, Protein

U2 - 10.1038/nature22070

DO - 10.1038/nature22070

M3 - Journal article

C2 - 28489817

SN - 0028-0836

VL - 545

SP - 317

EP - 322

JO - Nature

JF - Nature

IS - 7654

ER -