TY - JOUR
T1 - Critical Extracellular Ca2+Dependence of the Binding between PTH1R and a G-Protein Peptide Revealed by MD Simulations
AU - Li, Mengrong
AU - Bao, Yiqiong
AU - Xu, Ran
AU - La, Honggui
AU - Guo, Jingjing
N1 - Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.
PY - 2022/6/1
Y1 - 2022/6/1
N2 - The parathyroid hormone type 1 receptor (PTH1R), a canonical class B GPCR, is regulated by a positive allosteric modulator, extracellular Ca2+. Calcium ions prolong the residence time of PTH on the PTH1R, leading to increased receptor activation and duration of cAMP signaling. But the essential mechanism of the allosteric behavior of PTH1R is not fully understood. Here, extensive molecular dynamics (MD) simulations are performed for the PTH1R-G-protein combinations with and without Ca2+to describe how calcium ions allosterically engage receptor-G-protein coupling. We find that the binding of Ca2+stabilizes the conformation of the PTH1R-PTH-spep (the α5 helix of Gs protein) complex, especially the extracellular loop 1 (ECL1). Moreover, the MM-GBSA result indicates that Ca2+allosterically promotes the interaction between PTH1R and spep, consistent with the observation of steered molecular dynamics (SMD) simulations. We further illuminate the possible allosteric signaling pathway from the stable Ca2+-coupling site to the intracellular G-protein binding site. These results unveil structural determinants for Ca2+allosterism in the PTH1R-PTH-spep complex and give insights into pluridimensional GPCR signaling regulated by calcium ions.
AB - The parathyroid hormone type 1 receptor (PTH1R), a canonical class B GPCR, is regulated by a positive allosteric modulator, extracellular Ca2+. Calcium ions prolong the residence time of PTH on the PTH1R, leading to increased receptor activation and duration of cAMP signaling. But the essential mechanism of the allosteric behavior of PTH1R is not fully understood. Here, extensive molecular dynamics (MD) simulations are performed for the PTH1R-G-protein combinations with and without Ca2+to describe how calcium ions allosterically engage receptor-G-protein coupling. We find that the binding of Ca2+stabilizes the conformation of the PTH1R-PTH-spep (the α5 helix of Gs protein) complex, especially the extracellular loop 1 (ECL1). Moreover, the MM-GBSA result indicates that Ca2+allosterically promotes the interaction between PTH1R and spep, consistent with the observation of steered molecular dynamics (SMD) simulations. We further illuminate the possible allosteric signaling pathway from the stable Ca2+-coupling site to the intracellular G-protein binding site. These results unveil structural determinants for Ca2+allosterism in the PTH1R-PTH-spep complex and give insights into pluridimensional GPCR signaling regulated by calcium ions.
KW - allosteric regulation
KW - calcium ion allostery
KW - class B GPCR
KW - molecular dynamics simulation
KW - molecular modeling
KW - parathyroid hormone type 1 receptor
UR - http://www.scopus.com/inward/record.url?scp=85130844484&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.2c00176
DO - 10.1021/acschemneuro.2c00176
M3 - Article
C2 - 35543321
AN - SCOPUS:85130844484
SN - 1948-7193
VL - 13
SP - 1666
EP - 1674
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 11
ER -