2019 AMI Online Salon

Novel GPR40 Lipid-Facing Binding Pocket

Project Details

  • Entrant Name: Paul Veach

  • Membership Type: Student Submission

  • Other Contributors:

  • Address: Roseville,MN

  • Client: University of Illinois, Chicago

  • Medium/software used: Autodesk 3DS Max, Visual Molecular Dynamics, Pixologic ZBrush, Adobe After Effects, Adobe Illustrator

  • Final presentation format: Print poster

  • Primary Audience: Pharmacology researchers, students

Project Description

The GPR40 receptor’s AgoPAM binding pocket presents the first instance of a GPCR ligand entering its binding site through the lipid membrane. The AgoPAM and full agonist AP8 binds to this novel pocket, helping activate GPR40. The binding of partial agonist MK-8666 (to a different site) also helps regulate GPR40 activation to a lesser extent. These two ligands allosterically regulate GPR40 activation, with full agonist AP8 being the stronger driver of activation. Surface representations of GPR40 and the membrane and CPK representations of the ligands were used to show the spatial relationships between the binding pocket, ligands, and membrane. The insets show the binding mechanism of AP8. When AP8 binds to the AgoPAM site, a conformational change in ICL2 occurs, facilitating a number of interactions between AP8 and residues that situate AP8 in the binding pocket. A ribbon representation was used to simplify the receptor and place focus on the binding residues and AP8 in these insets.