| Structural highlights
Function
GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1]
Publication Abstract from PubMed
G-protein-coupled receptors (GPCRs) transmit downstream signals predominantly via G-protein pathways. However, the conformational basis of selective coupling of primary G-protein remains elusive. Histamine receptors H(2)R and H(3)R couple with G(s)- or G(i)-proteins respectively. Here, three cryo-EM structures of H(2)R-G(s) and H(3)R-G(i) complexes are presented at a global resolution of 2.6-2.7 A. These structures reveal the unique binding pose for endogenous histamine in H(3)R, wherein the amino group interacts with E206(5.46) of H(3)R instead of the conserved D114(3.32) of other aminergic receptors. Furthermore, comparative analysis of the H(2)R-G(s) and H(3)R-G(i) complexes reveals that the structural geometry of TM5/TM6 determines the primary G-protein selectivity in histamine receptors. Machine learning (ML)-based structuromic profiling and functional analysis of class A GPCR-G-protein complexes illustrate that TM5 length, TM5 tilt, and TM6 outward movement are key determinants of the G(s) and G(i/o) selectivity among the whole Class A family. Collectively, the findings uncover the common structural geometry within class A GPCRs that determines the primary G(s)- and G(i/o)-coupling selectivity.
Molecular Determinant Underlying Selective Coupling of Primary G-Protein by Class A GPCRs.,Shen Q, Tang X, Wen X, Cheng S, Xiao P, Zang SK, Shen DD, Jiang L, Zheng Y, Zhang H, Xu H, Mao C, Zhang M, Hu W, Sun JP, Zhang Y, Chen Z Adv Sci (Weinh). 2024 Apr 22:e2310120. doi: 10.1002/advs.202310120. PMID:38647423[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Johnston CA, Kimple AJ, Giguere PM, Siderovski DP. Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. Structure. 2008 Jul;16(7):1086-94. PMID:18611381 doi:http://dx.doi.org/10.1016/j.str.2008.04.010
- ↑ Shen Q, Tang X, Wen X, Cheng S, Xiao P, Zang SK, Shen DD, Jiang L, Zheng Y, Zhang H, Xu H, Mao C, Zhang M, Hu W, Sun JP, Zhang Y, Chen Z. Molecular Determinant Underlying Selective Coupling of Primary G-Protein by Class A GPCRs. Adv Sci (Weinh). 2024 Apr 22:e2310120. PMID:38647423 doi:10.1002/advs.202310120
|
