7YQE

Structure of human SRC regulatory domains in complex with the C-terminal PRRP motifs of GPR54.

7YQE の概要

• エントリーDOI: 10.2210/pdb7yqe/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src,KiSS-1 receptor (1 entity in total)
• 機能のキーワード: protein kinase-like, signaling, complex, signaling protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 42809.82

構造登録者

Song, G.,Xu, S. (登録日: 2022-08-06, 公開日: 2023-08-16, 最終更新日: 2026-03-04)

主引用文献

Li, Z.,Yang, X.,Fu, R.,Wu, Z.,Xu, S.,Jiao, J.,Qian, M.,Zhang, L.,Wu, C.,Xie, T.,Yao, J.,Wu, Z.,Li, W.,Ma, G.,You, Y.,Chen, Y.,Zhang, H.K.,Cheng, Y.,Tang, X.,Wu, P.,Lian, G.,Wei, H.,Zhao, J.,Xu, J.,Ai, L.,Siwko, S.,Wang, Y.,Ding, J.,Song, G.,Luo, J.,Liu, M.,Xiao, J.
Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of Src.
Nat Commun, 15:1300-1300, 2024

PubMed Abstract: Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18. Kiss1, Gpr54 and Dusp18 knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.

PubMed: 38346942
DOI: 10.1038/s41467-024-44852-9

実験手法

X-RAY DIFFRACTION (3.5 Å)