TY - JOUR
T1 - Quantifying conformational changes in GPCRs: Glimpse of a common functional mechanism
AU - Dalton, James A.R.
AU - Lans, Isaias
AU - Giraldo, Jesús
PY - 2015/12/12
Y1 - 2015/12/12
N2 - © 2015 Dalton et al.; licensee BioMed Central. Background: G-protein-coupled receptors (GPCRs) are important drug targets and a better understanding of their molecular mechanisms would be desirable. The crystallization rate of GPCRs has accelerated in recent years as techniques have become more sophisticated, particularly with respect to Class A GPCRs interacting with G-proteins. These developments have made it possible for a quantitative analysis of GPCR geometrical features and binding-site conformations, including a statistical comparison between Class A GPCRs in active (agonist-bound) and inactive (antagonist-bound) states. Results: Here we implement algorithms for the analysis of interhelical angles, distances, interactions and binding-site volumes in the transmembrane domains of 25 Class A GPCRs (7 active and 18 inactive). Two interhelical angles change in a statistically significant way between average inactive and active states: TM3-TM6 (by -9°) and TM6-TM7 (by +12°). A third interhelical angle: TM5-TM6 shows a trend, changing by -9°. In the transition from inactive to active states, average van der Waals interactions between TM3 and TM7 significantly increase as the average distance between them decreases by >2 Å. Average H-bonding between TM3 and TM6 decreases but is seemingly compensated by an increase in H-bonding between TM5 and TM6. In five Class A GPCRs, crystallized in both active and inactive states, increased H-bonding of agonists to TM6 and TM7, relative to antagonists, is observed. These protein-agonist interactions likely favour a change in the TM6-TM7 angle, which creates a narrowing in the binding pocket of activated receptors and an average ~200 Å3 reduction in volume. Conclusions: In terms of similar conformational changes and agonist binding pattern, Class A GPCRs appear to share a common mechanism of activation, which can be exploited in future drug development.
AB - © 2015 Dalton et al.; licensee BioMed Central. Background: G-protein-coupled receptors (GPCRs) are important drug targets and a better understanding of their molecular mechanisms would be desirable. The crystallization rate of GPCRs has accelerated in recent years as techniques have become more sophisticated, particularly with respect to Class A GPCRs interacting with G-proteins. These developments have made it possible for a quantitative analysis of GPCR geometrical features and binding-site conformations, including a statistical comparison between Class A GPCRs in active (agonist-bound) and inactive (antagonist-bound) states. Results: Here we implement algorithms for the analysis of interhelical angles, distances, interactions and binding-site volumes in the transmembrane domains of 25 Class A GPCRs (7 active and 18 inactive). Two interhelical angles change in a statistically significant way between average inactive and active states: TM3-TM6 (by -9°) and TM6-TM7 (by +12°). A third interhelical angle: TM5-TM6 shows a trend, changing by -9°. In the transition from inactive to active states, average van der Waals interactions between TM3 and TM7 significantly increase as the average distance between them decreases by >2 Å. Average H-bonding between TM3 and TM6 decreases but is seemingly compensated by an increase in H-bonding between TM5 and TM6. In five Class A GPCRs, crystallized in both active and inactive states, increased H-bonding of agonists to TM6 and TM7, relative to antagonists, is observed. These protein-agonist interactions likely favour a change in the TM6-TM7 angle, which creates a narrowing in the binding pocket of activated receptors and an average ~200 Å3 reduction in volume. Conclusions: In terms of similar conformational changes and agonist binding pattern, Class A GPCRs appear to share a common mechanism of activation, which can be exploited in future drug development.
KW - Conformational change
KW - Dihedral angle
KW - GPCR
KW - Interhelical interaction
KW - Quantify
KW - Receptor activation
U2 - 10.1186/s12859-015-0567-3
DO - 10.1186/s12859-015-0567-3
M3 - Article
SN - 1471-2105
VL - 16
JO - BMC Bioinformatics
JF - BMC Bioinformatics
M1 - 124
ER -