PLEASE ANSWER ALL PARTS Chapter 12 GPCRs constitute a major class of drug target
ID: 176230 • Letter: P
Question
PLEASE ANSWER ALL PARTS
Chapter 12
GPCRs constitute a major class of drug targets and modulating their signaling can produce a wide range of pharmacological outcomes. With the growing number of high-resolution GPCR crystal structures, we have the unprecedented opportunity to leverage structure-based drug design techniques.
A. Describe the structure and functionality of GPCRs and identify the commonly druggable sites on the protein.
B. Describe the types of ligands that commonly bind GPCRs.
C. Describe techniques that are used to study drug interactions with GPCRs.
Explanation / Answer
A) G protein-coupled receptors (GPCRs) comprise the largest family of proteins targeted by drug discovery. New developments in the area of X-ray crystallography suggest that the structural veil has now lifted and that we are on the threshold of a new era for GPCR drug discovery. GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) -helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors(mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain.
Function: For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins.[38] In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called -arrestins (-arr).[39] Once bound, -arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the -arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization.
Entity of “druggable” targets is still active. Basic approaches employed to explore the issue include 1) tissue expression profiling (including comparisons between healthy and disease states); 2) searching for regulation of transcripts and gene copies in disease models through microarray, quantitative polymerase chain reaction, and genomic deep sequencing analyses; 3) establishing gene-disease linkage through chromosome mapping and phenotypic analysis of transgenic animals; and 4) conducting in vivo/in vitro pharmacological studies with target-active prelead molecules when available. Absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic (PK) studies are increasingly being employed early on in the drug discovery process to assist in the interpretation of ongoing and future in vivo experimentation.
b) The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters, and vary in size from small molecules to peptides to large proteins.
C) The introduction of recombinant cell lines expressing a single GPCR type has been a big step forward for studying both drug-receptor interactions and signal transduction.
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