Cryo-EM Structure of the Human Histamine H Receptor/G Complex

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Apr 8

PMID 33828102

Citations 55

Authors

Ruixue Xia

Na Wang

Zhenmei Xu

Yang Lu

Jing Song

Anqi Zhang

Changyou Guo

Yuanzheng He

Affiliations

Soon will be listed here.

Abstract

Histamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human HR in complex with a G protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for G engagement in a model of "squash to activate and expand to deactivate". The structure also reveals features for G coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of G protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.

Citing Articles

Histamine-modulated wettability switching in G-protein-coupled receptor inspired nanochannel for potential drug screening and biosensing.

Zhao Q, Ran X, Yan Z, Qian H, Yan X Nat Commun. 2025; 16(1):1820.

PMID: 39979281 PMC: 11842845. DOI: 10.1038/s41467-025-57064-6.

Molecular mechanism of ligand recognition and activation of lysophosphatidic acid receptor LPAR6.

Duan Y, Xu Z, Hao B, Zhang A, Guo C, He Y Proc Natl Acad Sci U S A. 2025; 122(4):e2415426122.

PMID: 39847322 PMC: 11789011. DOI: 10.1073/pnas.2415426122.

Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling.

Wang L, Hu F, Cui Q, Qiao H, Li L, Geng T Nat Commun. 2025; 16(1):362.

PMID: 39753551 PMC: 11698847. DOI: 10.1038/s41467-024-55431-3.

Probing the Histamine H Receptor Binding Site to Explore Ligand Binding Kinetics.

Kuhne S, Bosma R, Kooistra A, Riemens R, Stroet M, Vischer H J Med Chem. 2024; 68(1):448-464.

PMID: 39723903 PMC: 11726634. DOI: 10.1021/acs.jmedchem.4c02043.

Coupling and Activation of the β1 Adrenergic Receptor - The Role of the Third Intracellular Loop.

Qiu X, Chao K, Song S, Wang Y, Chen Y, Rouse S J Am Chem Soc. 2024; .

PMID: 39359104 PMC: 11487556. DOI: 10.1021/jacs.4c11250.

References

Nishimura A, Kitano K, Takasaki J, Taniguchi M, Mizuno N, Tago K . Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule. Proc Natl Acad Sci U S A. 2010; 107(31):13666-71. PMC: 2922266. DOI: 10.1073/pnas.1003553107. View

Duan J, Shen D, Zhou X, Bi P, Liu Q, Tan Y . Cryo-EM structure of an activated VIP1 receptor-G protein complex revealed by a NanoBiT tethering strategy. Nat Commun. 2020; 11(1):4121. PMC: 7431577. DOI: 10.1038/s41467-020-17933-8. View

Tashiro M, Kato M, Miyake M, Watanuki S, Funaki Y, Ishikawa Y . Dose dependency of brain histamine H(1) receptor occupancy following oral administration of cetirizine hydrochloride measured using PET with [11C]doxepin. Hum Psychopharmacol. 2009; 24(7):540-8. DOI: 10.1002/hup.1051. View

Flock T, Hauser A, Lund N, Gloriam D, Balaji S, Babu M . Selectivity determinants of GPCR-G-protein binding. Nature. 2017; 545(7654):317-322. PMC: 5846738. DOI: 10.1038/nature22070. View

Kumar K, Shalev-Benami M, Robertson M, Hu H, Banister S, Hollingsworth S . Structure of a Signaling Cannabinoid Receptor 1-G Protein Complex. Cell. 2019; 176(3):448-458.e12. PMC: 6461403. DOI: 10.1016/j.cell.2018.11.040. View

Harding S, Sharman J, Faccenda E, Southan C, Pawson A, Ireland S . The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 2017; 46(D1):D1091-D1106. PMC: 5753190. DOI: 10.1093/nar/gkx1121. View

Zivanov J, Nakane T, Scheres S . A Bayesian approach to beam-induced motion correction in cryo-EM single-particle analysis. IUCrJ. 2019; 6(Pt 1):5-17. PMC: 6327179. DOI: 10.1107/S205225251801463X. View

Bjarnadottir T, Gloriam D, Hellstrand S, Kristiansson H, Fredriksson R, Schioth H . Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse. Genomics. 2006; 88(3):263-73. DOI: 10.1016/j.ygeno.2006.04.001. View

Maeda S, Koehl A, Matile H, Hu H, Hilger D, Schertler G . Development of an antibody fragment that stabilizes GPCR/G-protein complexes. Nat Commun. 2018; 9(1):3712. PMC: 6137068. DOI: 10.1038/s41467-018-06002-w. View

10.

Pandy-Szekeres G, Munk C, Tsonkov T, Mordalski S, Harpsoe K, Hauser A . GPCRdb in 2018: adding GPCR structure models and ligands. Nucleic Acids Res. 2017; 46(D1):D440-D446. PMC: 5753179. DOI: 10.1093/nar/gkx1109. View

11.

Fein M, Fischer D, OKeefe A, Sussman G . CSACI position statement: Newer generation H-antihistamines are safer than first-generation H-antihistamines and should be the first-line antihistamines for the treatment of allergic rhinitis and urticaria. Allergy Asthma Clin Immunol. 2019; 15:61. PMC: 6771107. DOI: 10.1186/s13223-019-0375-9. View

12.

Monczor F, Fernandez N . Current Knowledge and Perspectives on Histamine H1 and H2 Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands. Mol Pharmacol. 2016; 90(5):640-648. DOI: 10.1124/mol.116.105981. View

13.

Kim K, Che T, Panova O, DiBerto J, Lyu J, Krumm B . Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor. Cell. 2020; 182(6):1574-1588.e19. PMC: 7593816. DOI: 10.1016/j.cell.2020.08.024. View

14.

Fung-Leung W, Thurmond R, Ling P, Karlsson L . Histamine H4 receptor antagonists: the new antihistamines?. Curr Opin Investig Drugs. 2004; 5(11):1174-83. View

15.

Robert X, Gouet P . Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res. 2014; 42(Web Server issue):W320-4. PMC: 4086106. DOI: 10.1093/nar/gku316. View

16.

Rosenbaum D, Zhang C, Lyons J, Holl R, Aragao D, Arlow D . Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature. 2011; 469(7329):236-40. PMC: 3074335. DOI: 10.1038/nature09665. View

17.

Shimamura T, Shiroishi M, Weyand S, Tsujimoto H, Winter G, Katritch V . Structure of the human histamine H1 receptor complex with doxepin. Nature. 2011; 475(7354):65-70. PMC: 3131495. DOI: 10.1038/nature10236. View

18.

Xing C, Zhuang Y, Xu T, Feng Z, Zhou X, Chen M . Cryo-EM Structure of the Human Cannabinoid Receptor CB2-G Signaling Complex. Cell. 2020; 180(4):645-654.e13. PMC: 8247115. DOI: 10.1016/j.cell.2020.01.007. View

19.

Maeda S, Qu Q, Robertson M, Skiniotis G, Kobilka B . Structures of the M1 and M2 muscarinic acetylcholine receptor/G-protein complexes. Science. 2019; 364(6440):552-557. PMC: 7034192. DOI: 10.1126/science.aaw5188. View

20.

Zhou F, Zhang H, Cong Z, Zhao L, Zhou Q, Mao C . Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020; 11(1):5205. PMC: 7567103. DOI: 10.1038/s41467-020-18945-0. View