GPCR agonist binding revealed by modeling and crystallography

Abstract

While structural coverage of the G-protein coupled receptor (GPCR) family steadily improves, high plasticity of these membrane proteins poses additional challenges for crystallographic studies of their complexes with different classes of ligands, especially agonists. Ability to computationally predict binding of natural and clinically relevant agonists and corresponding changes in the receptor pocket, starting from inactive GPCR structures, is therefore of great interest for understanding GPCR biology and drug action. Comparison of published in 2009 and 2010 computational models with recently determined agonist-bound structures of β-adrenergic and adenosine A2A receptors reveals high accuracy of the predicted agonist binding poses (0.8 Å and 1.7 Å respectively) and receptor interactions. In the case of the β2AR, energy-based models with limited backbone flexibility also allowed characterization of side chain rotations and a finite backbone shift in the pocket region as determinants of full, partial or inverse agonism. Development of accurate models of agonist binding for other GPCRs will be instrumental for functional and pharmacological studies, complementing biochemical and crystallographic techniques.

From Receptors to Ligands: Fragment-assisted Drug Design for GPCRs Applied to the Discovery of H3 and H4 Receptor Antagonists

“…The results reported here are comparable to those from other similar works [19][20][21][22] which showed that GPCR modeling [23][24][25][26][27][28][29][30][31] in the absence of a crystal structure can be a valid replacement [32][33][34][35][36][37][38][39] for structural and functional exploration of GPCR receptors, and for the discovery [21,[40][41][42][43], VS [44][45][46][47][48][49][50][51][52] and optimisation [23,53] of their ligands.…”

Histidine7.36(305) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation

“…The residue in position 7.39 forms part of both the consensus ligand binding pocket and the interhelical network and thus potentially couples binding of diverse ligands with the conserved receptor structure (Venkatakrishnan et al, 2013). Crystal agonists, agonist interactions with residues in TM3, TM5, TM6 and TM7 cause small (in the cases of rhodopsin, β adrenergic and adenosine receptors) or large (in the cases of muscarinic and purinergic receptors) changes in the ligand binding pocket that draw the extracellular ends of these helices together and contract the pockets of receptors that bind dissociable ligands, but widen the retinal pocket in rhodopsin (Deupi et al, 2012a;Deupi et al, 2012b;Katritch and Abagyan, 2011;Kruse et al, 2013;Lebon et al, 2012;Rasmussen et al, 2011a;Ring et al, 2013;Venkatakrishnan et al, 2013;Xu et al, 2011;Zhang et al, 2014a;Zhang et al, 2014b with residues in the cytosolic ends of TM3, TM5 and TM6 to stabilize the active receptor conformation (Deupi et al, 2012a;Deupi and Standfuss, 2011;Deupi et al, 2012b;Standfuss et al, 2011;Trzaskowski et al, 2012;Venkatakrishnan et al, 2013). It is notable that the key receptor residues that mediate agonist activity differ.…”

“…It is notable that the key receptor residues that mediate agonist activity differ. In the β 2 adrenergic receptor the TM5 Ser 5.42 and Ser 5.46 residues are key for agonist activity, whereas the TM7 residues, Ser 7.42 and His 7.43 , are key for activation of the A 2A adenosine receptor (Katritch and Abagyan, 2011;Lebon et al, 2012;Xu et al, 2011). Similarly, agonist ligands interact directly with Trp 6.48 and Tyr 6.51 (in the CWxPY motif) of rhodopsin and the A 2A adenosine…”

G-Protein Coupled Receptors: Experimental and Computational Approaches

“…& Kobilka, B. 2007;Katritch, V. et al 2011) In contrast to rhodopsin where more information is present for the activation state of the molecule, in case of the other GPCRs much less is known about agonist induced conformational changes that occur during the activation of the receptor. (Wess, J., Han, S. J., Kim, S. K., Jacobson, K. A., & Li, J. H. 2008) The most similar parts for the GPCRs are the cytoplasmic ends of the TM segments adjacent to the second and third cytoplasmic domains which interact with G protein.…”

“…The intrinsic plasticity of GPCRs is a major problem in using their inactive state for agonist design in drug discovery. (Katritch, V. et al 2011) …”