7YQE
Structure of human SRC regulatory domains in complex with the C-terminal PRRP motifs of GPR54.
Summary for 7YQE
| Entry DOI | 10.2210/pdb7yqe/pdb |
| Descriptor | Proto-oncogene tyrosine-protein kinase Src,KiSS-1 receptor (1 entity in total) |
| Functional Keywords | protein kinase-like, signaling, complex, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 42809.82 |
| Authors | |
| Primary citation | 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 Cited by 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: 38346942DOI: 10.1038/s41467-024-44852-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.5 Å) |
Structure validation
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