Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations

Abstract

Graphical Abstract Highlights d Intracellular conformational changes of the angiotensin receptor monitored by DEER d Different functional classes of ligands stabilize distinct sets of conformations d Gq-and b-arrestin-biased ligands have opposing effects relative to angiotensin II d Maps of conformations suggest a structural basis for biased ligand signaling

GPCRmd uncovers the dynamics of the 3D-GPCRome

“…However, a growing body of research suggests that GPCRs are not two-or three-state systems but exhibit a wide range of conformational states with sometimes subtle yet important differences. While several experimental techniques such as nuclear magnetic resonance (NMR) 36 , double electron-electron resonance (DEER) 37 , or single-molecule fluorescence energy transfer (smFRET) 38 We have demonstrated the utility of the GPCRmd platform by performing comparative analyses across multiple receptors of two relevant aspects of GPCR biology, namely water network and allosteric Na+ interaction analysis. Using GPCRmd tools, we pinpointed differences in the water-mediated networks of the OX2R and the β2AR potentially involved in receptor activation and G protein coupling.…”

Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells

“…GPCRs signal by allostery, and were considered for many years to operate as binary switches that bind to cognate transducer and regulator proteins in a single agonist-induced activated state. Over the past decade an expanded view has taken hold, supported by accumulating in vitro evidence that GPCRs are conformationally flexible [1][2][3][4][5] and a confluence of cell biological and in vivo evidence supporting the existence of functionally selective agonist effects [6][7][8] . According to this still-evolving view, agonists have the potential to promote GPCRs to selectively recruit one transducer or regulator protein over another, introducing bias into the signaling cascade at a receptor-proximal level that is either propagated downstream or eliminated during intermediate transduction steps 9,10 .…”

In silico prediction of ARB resistance: A first step in creating personalized ARB therapy

“…The empty AT 1 R model is the third ligand-free molecular dynamics derived model created after the AT 1 R was crystallized. (14,17) In the crystalized AT 1 Rs (4ZUD and 4YAY) Arg167 points toward the ligand-binding pocket; (7,8) however, unpublished homology modeling followed by MD simulation of the AT 1 R from our group and similarly published studies orientate Arg167 away from the binding pocket. (18,19) Arg167 is essential for Ang II binding based on mutagenesis and modeling studies (7,11,17,20) and predicted to be essential for ARB binding based on the crystal structures and subsequent docking.…”

“…Throughout the simulations, the position of helix 8 varied by 12 angstroms from the empty AT 1 R model, which is similar to previous MD simulations. (14) To further address the overall movement of the simulations, distance measurements corresponding to double electron-electron resonance (DEER) spectroscopy of the AT 1 R (14) were measured over the last 20 ns of simulation ( Figure 1B). Red Xs represent the major modes of the DEER data in Figure 1B; 50% of the major modes from the DEER experiments are within distances observed in the modeled empty AT 1 R. Moreover, most of the measurements from the model lie within the range identified in the DEER spectroscopy data set but capture a different state than the MD modeling presented with the DEER spectroscopy.…”

“…The same measurements were made in the two AT 1 R crystal structures (4ZUD and 4YAY) and over the last 20 ns of each of the three replica MD simulations. Wingler et al conducted DEER spectroscopy of apo-AT 1 R,(14) similar measurements were made via measuring the distance between the center of mass of the residues examined in the DEER spectroscopy studies across the entire simulation utilizing CPPTRAJ (33).…”