Roughly twice as many pharmaceuticals target GPCRs versus nuclear receptors.Group of answer choicesTrueFalse

Which statement regarding GPCRs as drug targets is FALSE?Group of answer choicesThe most targeted GPCRs for drug development belong to nonrhodopsin class A.Beta blockers are beta1 adrenergic receptor antagonists that act to slow heart rate and force of contraction to treat hypertension.Orphan GPCRs are considered to have untapped potential as new drug targets.GPCRs as a family are only activated by amino acids and their derivatives like epinephrine, glutamate and dopamine.

Which of the following statements is (are) trueabout the G-protein coupled receptors (GPCRs)?A.There are only a few GPCRs in the human genome.B.When a signal molecule binds to the GPCR it causesphosphorylation of the GPCR that allows the G-proteinto bind.C.GPCRs act as GEFs for specific G-proteins.D.They are peripheral proteins composed of multiplepolypeptides.

Which of the following statements is TRUE regarding drug development strategies for RXR- heterodimer receptors?Group of answer choicesDevelopment of drugs for specific receptor isoforms must always be designed to interact with amino acids outside the ligand binding domain, since the sequences in that domain are so similar between isoforms.It is possible to develop selective RXR binding drugs that target specific RXR-nuclear receptor heterodimers, despite the fact that RXRs interact with many different nuclear receptors.To develop drugs that target human RXR-heterodimer receptors, researchers only conduct their experiments with human receptors in human cell-based assays, since the structure and function of these receptors varies so widely across species.Since RXR heterodimer receptors are always found in the cytoplasm in the absence of hormone, a drug that inhibits ligand induced nuclear translocation would effectively block its activity.

The clinical application of drug-receptor interactions include: A. assessment and classification of new agonists TRUE/FALSE B. define ligand activity and selectivity in normal and diseased tissues TRUE/FALSE C. identify novel chemical structures/drugs that interact with receptors TRUE/FALSE D. identification and characterization of receptors transfected into cell lines TRUE/FALSE E. study receptor dynamics and localization TRUE/FALSE

The phenomenon of receptor bias refers to the selective signaling through a GPCR, mediated by either G protein or β-arrestin, due to mutations. Investigating thefunctional dynamics of biased receptors holds significant potential in elucidating the fundamentals of transducer selective signaling in GPCRs induced by biased ligands. In β2AR, a single mutation (Y2195.58A) selects against GRK binding, thus, disfavoring the association with β-arrestins, leading to G protein bias of the receptor.18 Whereas, a triple mutation (T682.39F, Y1323.51G, and Y2195.58A) inhibits G protein signaling, consequently resulting in β-arrestin bias.17 In an attempt to understand the atomistic basis of this biased signaling in β2AR, we performed large-scale all-atom enhanced sampling GaMD simulations and analyzed the allosteric conformational changes sampled by mutant receptors.Our observations reveal specific conformations of the transmembrane helices in the extracellular and cytosolic regions of the mutant receptors compared to the wild-type. In the single mutant, ICL3 mostly positions away from the transducer-binding cavity, sampling an open state that facilitates G protein binding. In contrast, the triple mutant prefers a closed state of the ICL3, thereby occluding the cavity for G protein engagement. Further, in the mutant receptors, the side chains of R1313.50 and Y3267.53 in the conserved motifs D(E)RY and NPxxY exhibit characteristic orientations that could enable specific transducer interactions. In particular, the β-arrestin-favoring triple mutant displays a relatively larger population of the downward rotameric state of R1313.50, characterized by a cytoplasm-facing side chain conformation that selectively facilitates the engagement of β-arrestin over G protein. By employing machine learning classification algorithms, we discern the inter-residue interactions that promote different orientations of R1313.50 and Y3267.53 in the wild-type and mutant systems. The evaluation of suboptimal paths reveals distinctive rewiring of allosteric communication pathways between the extracellular agonist BI-167107 and the residues in the interfaces of various transducers (G protein and GRK/β-arrestin). These allosteric reconfigurations drive specific conformational sampling, resulting in the selective engagement of transducers in both single and triple mutants. The critical residues identified in allosteric signal transfer for each β2AR mutant present promising opportunities for future experimental and computational investigations that could target the sites to unravel the allosteric mechanisms underlying biased signaling across various other GPCRs. Moreover, the atomistic insights presented here may help in developing therapeutic strategies for diseases caused by mutations in GPCRs and aid in designing biased drugs that target these receptors with fewer side effects and better efficacy.