A Functional Selectivity Mechanism at the Serotonin-2A GPCR Involves Ligand-Dependent Conformations of Intracellular Loop 2
被引:59
作者:
Perez-Aguilar, Jose Manuel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Perez-Aguilar, Jose Manuel
[1
]
Shan, Jufang
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Shan, Jufang
[1
]
LeVine, Michael V.
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
LeVine, Michael V.
[1
]
Khelashvili, George
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USACornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Khelashvili, George
[1
]
Weinstein, Harel
论文数: 0引用数: 0
h-index: 0
机构:
Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USACornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
Weinstein, Harel
[1
,2
]
机构:
[1] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA
[2] Cornell Univ, Weill Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10065 USA
With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT2AR activation.
Ballesteros J. A., 1995, Neuroscience Methods, V25, P366, DOI [10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471]
Ballesteros J. A., 1995, Neuroscience Methods, V25, P366, DOI [10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471(05)80049-7, DOI 10.1016/S1043-9471]