变构调节
甲状旁腺激素
化学
受体
跨膜结构域
变构酶
生物物理学
甲状旁腺激素受体
变构调节剂
钙敏感受体
生物化学
立体化学
钙
生物
激素受体
遗传学
癌症
有机化学
乳腺癌
作者
Mengrong Li,Miaomiao Li,Jingjing Guo
标识
DOI:10.1021/acs.jcim.1c00471
摘要
Parathyroid hormone (PTH) is an endogenous ligand that activates the PTH type 1 receptor (PTH1R) signaling. Ca2+, a common second messenger, acts as an allosteric regulator for prolonging the activation of PTH1R. However, a clear picture of the underlying allosteric mechanism is still missing. Herein, extensive molecular dynamics (MD) simulations are performed for PTH1R-PTH complexes with and without Ca2+ ions, allowing us to delineate the molecular details of calcium-induced allostery. Our results indicate that acidic residues in the extracellular loop 1 (ECL1) (D251, E252, E254, and E258–E260) and PTH (E19 and E22) serve as key determinants for local Ca2+-coupling structures and rigidity of ECL1. Moreover, the binding of Ca2+ induces conformational changes of transmembrane domain 6/7 (TM6/7) that are related to PTH1R activation and strengthens the residue–residue communication within PTH and TMD allosterically. Moreover, our results demonstrate that the presence of Ca2+ ions potentiates the interaction between PTH and PTH1R via steered molecular dynamics (SMD) simulations, while the point mutation in the PTH (PTHR25C) weakens the binding of PTH and PTH1R. These results support that Ca2+ ions might further prolong the residence time of PTH on PTH1R and facilitate the positive allostery of PTH1R. Together, the present work provides new insights into the allosteric regulation mechanism of GPCRs induced by ions and related drug design targeting the PTH1R allosteric pathway.
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