GPCR Conformational Analysis using the Knob-Socket Model
Poster Number
24A
Format
Poster Presentation
Faculty Mentor Name
Jerry Tsai
Faculty Mentor Department
Chemistry
Abstract/Artist Statement
The G protein-coupled receptors (GPCRs) are a widespread family of transmembrane receptors that have become a highly successful class of targets for therapeutic drugs. GPCRs play a vital role in many physiological processes, such as sensory perception, hormone regulation, neurotransmission, and immunity. Furthermore, the misregulation of GPCRs has been implicated in numerous diseases, including hypertension, diabetes, asthma, and cancer, making it a target for drug development. Functionally, upon binding of a ligand, GPCRs undergo conformational changes that result in the rotation of transmembrane helix six (TM6) and formation of a hydrophobic bubble in the membrane. This bubble allows the signal transducer, G-protein, to bind and initiate a cascade of events that activate or inhibit effector proteins. To better understand the protein architecture of the GPCR, this study expands upon the knob-socket (KS) model by categorizing the interactions between a single knob residue and a group of contiguous sockets, or a pocket consisting of four or more residues. The KS analysis will be performed on X-Ray crystal structures of the cannabinoid receptor (CB₁), and comparisons of packing patterns between the GPCR in various bound states will be compared. Computational analysis found that TM6 moved outwards because of a closed socket found in the helix whereas conserved motifs in TM4, TM5 and TM7 moved inwards. Furthermore, TM3, TM4, TM5 and TM6 packed into the Gα subunit of the G-Protein, with TM3 and TM5 having the most interface interaction.
Location
Information Commons, William Knox Holt Memorial Library and Learning Center
Start Date
29-4-2023 10:00 AM
End Date
29-4-2023 1:00 PM
GPCR Conformational Analysis using the Knob-Socket Model
Information Commons, William Knox Holt Memorial Library and Learning Center
The G protein-coupled receptors (GPCRs) are a widespread family of transmembrane receptors that have become a highly successful class of targets for therapeutic drugs. GPCRs play a vital role in many physiological processes, such as sensory perception, hormone regulation, neurotransmission, and immunity. Furthermore, the misregulation of GPCRs has been implicated in numerous diseases, including hypertension, diabetes, asthma, and cancer, making it a target for drug development. Functionally, upon binding of a ligand, GPCRs undergo conformational changes that result in the rotation of transmembrane helix six (TM6) and formation of a hydrophobic bubble in the membrane. This bubble allows the signal transducer, G-protein, to bind and initiate a cascade of events that activate or inhibit effector proteins. To better understand the protein architecture of the GPCR, this study expands upon the knob-socket (KS) model by categorizing the interactions between a single knob residue and a group of contiguous sockets, or a pocket consisting of four or more residues. The KS analysis will be performed on X-Ray crystal structures of the cannabinoid receptor (CB₁), and comparisons of packing patterns between the GPCR in various bound states will be compared. Computational analysis found that TM6 moved outwards because of a closed socket found in the helix whereas conserved motifs in TM4, TM5 and TM7 moved inwards. Furthermore, TM3, TM4, TM5 and TM6 packed into the Gα subunit of the G-Protein, with TM3 and TM5 having the most interface interaction.