TY - JOUR
T1 - The structural determinants of the bitopic binding mode of a negative allosteric modulator of the dopamine D2 receptor
AU - Draper-Joyce, Christopher J.
AU - Michino, Mayako
AU - Verma, Ravi Kumar
AU - Klein Herenbrink, Carmen
AU - Shonberg, Jeremy
AU - Kopinathan, Anitha
AU - Scammells, Peter J.
AU - Capuano, Ben
AU - Thal, David M.
AU - Javitch, Jonathan A.
AU - Christopoulos, Arthur
AU - Shi, Lei
AU - Lane, J. Robert
PY - 2018/2/1
Y1 - 2018/2/1
N2 - SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E952.65) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D2R with tailored competitive versus allosteric properties.
AB - SB269652 is a negative allosteric modulator of the dopamine D2 receptor (D2R) yet possesses structural similarity to ligands with a competitive mode of interaction. In this study, we aimed to understand the ligand-receptor interactions that confer its allosteric action. We combined site-directed mutagenesis with molecular dynamics simulations using both SB269652 and derivatives from our previous structure activity studies. We identify residues within the conserved orthosteric binding site (OBS) and a secondary binding pocket (SBP) that determine affinity and cooperativity. Our results indicate that interaction with the SBP is a requirement for allosteric pharmacology, but that both competitive and allosteric derivatives of SB269652 can display sensitivity to the mutation of a glutamate residue (E952.65) within the SBP. Our findings provide the molecular basis for the differences in affinity between SB269652 derivatives, and reveal how changes to interactions made by the primary pharmacophore of SB269652 in the orthosteric pocket can confer changes in the interactions made by the secondary pharmacophore in the SBP. Our insights provide a structure-activity framework towards rational optimization of bitopic ligands for D2R with tailored competitive versus allosteric properties.
KW - Allosteric modulation
KW - Bitopic ligands
KW - Dopamine receptor
KW - G protein-coupled receptor
KW - Molecular dynamics simulations
KW - Mutagenesis
UR - http://www.scopus.com/inward/record.url?scp=85041575572&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2018.01.002
DO - 10.1016/j.bcp.2018.01.002
M3 - Article
AN - SCOPUS:85041575572
SN - 0006-2952
VL - 148
SP - 315
EP - 328
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
ER -