G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a similar to 110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only similar to 24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.
机构:
Fac Med Strasbourg, Lab Neurobiol & Pharmacol Cardiovasc, Strasbourg, FranceFac Med Strasbourg, Lab Neurobiol & Pharmacol Cardiovasc, Strasbourg, France
Ayadi, T.
Monassier, L.
论文数: 0引用数: 0
h-index: 0
机构:
Fac Med Strasbourg, Lab Neurobiol & Pharmacol Cardiovasc, Strasbourg, FranceFac Med Strasbourg, Lab Neurobiol & Pharmacol Cardiovasc, Strasbourg, France
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
John D. McCorvy
Daniel Wacker
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Daniel Wacker
Sheng Wang
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Sheng Wang
Bemnat Agegnehu
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Bemnat Agegnehu
Jing Liu
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Jing Liu
Katherine Lansu
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Katherine Lansu
Alexandra R. Tribo
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Alexandra R. Tribo
Reid H. J. Olsen
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Reid H. J. Olsen
Tao Che
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Tao Che
Jian Jin
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry
Jian Jin
Bryan L. Roth
论文数: 0引用数: 0
h-index: 0
机构:University of North Carolina Chapel Hill Medical School,National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology and Division of Chemical Biology and Medicinal Chemistry