TY - JOUR
T1 - GDP Release from the Open Conformation of Gα Requires Allosteric Signaling from the Agonist-Bound Human β2Adrenergic Receptor
AU - Kumar, Vikash
AU - Hoag, Hannah
AU - Sader, Safaa
AU - Scorese, Nicolas
AU - Liu, Haiguang
AU - Wu, Chun
N1 - Funding Information:
C.W. acknowledges the support by Rowan SEED grant and the National Science Foundation under Grants NSF ACI-1429467/RUI-1904797, and XSEDE MCB 170088. The Anton2 machine at the Pittsburgh Supercomputing Center (PSCA17017P) was generously made available by D. E. Shaw Research. The grants from National Natural Science Foundation of China (11575021, U1930402) to H.L. are also acknowledged.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/8/24
Y1 - 2020/8/24
N2 - G-protein-coupled receptors (GPCRs) transmit signals into the cell in response to ligand binding at its extracellular domain, which is characterized by the coupling of agonist-induced receptor conformational change to guanine nucleotide (GDP) exchange with guanosine triphosphate on a heterotrimeric (αβÎ) guanine nucleotide-binding protein (G-protein), leading to the activation of the G-protein. The signal transduction mechanisms have been widely researched in vivo and in silico. However, coordinated communication from stimulating ligands to the bound GDP still remains elusive. In the present study, we used microsecond (μS) molecular dynamic (MD) simulations to directly probe the communication from the β2 adrenergic receptor (β2AR) with an agonist or an antagonist or no ligand to GDP bound to the open conformation of the Gα protein. Molecular mechanism-general Born surface area calculation results indicated either the agonist or the antagonist destabilized the binding between the receptor and the G-protein but the agonist caused a higher level of destabilization than the antagonist. This is consistent with the role of agonist in the activation of the G-protein. Interestingly, while GDP remained bound with the Gα-protein for the two inactive systems (antagonist-bound and apo form), GDP dissociated from the open conformation of the Gα protein for the agonist activated system. Data obtained from MD simulations indicated that the receptor and the Gα subunit play a big role in coordinated communication and nucleotide exchange. Based on residue interaction network analysis, we observed that engagement of agonist-bound β2AR with an α5 helix of Gα is essential for the GDP release and the residues in the phosphate-binding loop, α1 helix, and α5 helix play very important roles in the GDP release. The insights on GPCR-G-protein communication will facilitate the rational design of agonists and antagonists that target both active and inactive GPCR binding pockets, leading to more precise drugs.
AB - G-protein-coupled receptors (GPCRs) transmit signals into the cell in response to ligand binding at its extracellular domain, which is characterized by the coupling of agonist-induced receptor conformational change to guanine nucleotide (GDP) exchange with guanosine triphosphate on a heterotrimeric (αβÎ) guanine nucleotide-binding protein (G-protein), leading to the activation of the G-protein. The signal transduction mechanisms have been widely researched in vivo and in silico. However, coordinated communication from stimulating ligands to the bound GDP still remains elusive. In the present study, we used microsecond (μS) molecular dynamic (MD) simulations to directly probe the communication from the β2 adrenergic receptor (β2AR) with an agonist or an antagonist or no ligand to GDP bound to the open conformation of the Gα protein. Molecular mechanism-general Born surface area calculation results indicated either the agonist or the antagonist destabilized the binding between the receptor and the G-protein but the agonist caused a higher level of destabilization than the antagonist. This is consistent with the role of agonist in the activation of the G-protein. Interestingly, while GDP remained bound with the Gα-protein for the two inactive systems (antagonist-bound and apo form), GDP dissociated from the open conformation of the Gα protein for the agonist activated system. Data obtained from MD simulations indicated that the receptor and the Gα subunit play a big role in coordinated communication and nucleotide exchange. Based on residue interaction network analysis, we observed that engagement of agonist-bound β2AR with an α5 helix of Gα is essential for the GDP release and the residues in the phosphate-binding loop, α1 helix, and α5 helix play very important roles in the GDP release. The insights on GPCR-G-protein communication will facilitate the rational design of agonists and antagonists that target both active and inactive GPCR binding pockets, leading to more precise drugs.
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U2 - 10.1021/acs.jcim.0c00432
DO - 10.1021/acs.jcim.0c00432
M3 - Article
C2 - 32786510
AN - SCOPUS:85089805712
VL - 60
SP - 4064
EP - 4075
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
SN - 1549-9596
IS - 8
ER -