Structural Basis for Recognition of Antihistamine Drug by Human Histamine Receptor

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Oct 15

PMID 36243875

Authors

Xueqian Peng

Linlin Yang

Zixuan Liu

Siyi Lou

Shiliu Mei

Meiling Li

Zhong Chen

Haitao Zhang

Affiliations

Soon will be listed here.

Abstract

The histamine receptors belong to the G protein-coupled receptor (GPCR) superfamily, and play important roles in the regulation of histamine and other neurotransmitters in the central nervous system, as potential targets for the treatment of neurologic and psychiatric disorders. Here we report the crystal structure of human histamine receptor HR bound to an antagonist PF-03654746 at 2.6 Å resolution. Combined with the computational and functional assays, our structure reveals binding modes of the antagonist and allosteric cholesterol. Molecular dynamic simulations and molecular docking of different antihistamines further elucidate the conserved ligand-binding modes. These findings are therefore expected to facilitate the structure-based design of novel antihistamines.

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References

Xia R, Wang N, Xu Z, Lu Y, Song J, Zhang A . Cryo-EM structure of the human histamine H receptor/G complex. Nat Commun. 2021; 12(1):2086. PMC: 8027608. DOI: 10.1038/s41467-021-22427-2. View

Shao Z, Yan W, Chapman K, Ramesh K, Ferrell A, Yin J . Structure of an allosteric modulator bound to the CB1 cannabinoid receptor. Nat Chem Biol. 2019; 15(12):1199-1205. DOI: 10.1038/s41589-019-0387-2. View

Troxler T, Feuerbach D, Zhang X, Yang C, Lagu B, Perrone M . The Discovery of LML134, a Histamine H3 Receptor Inverse Agonist for the Clinical Treatment of Excessive Sleep Disorders. ChemMedChem. 2019; 14(13):1238-1247. DOI: 10.1002/cmdc.201900176. View

Chu R, Takei J, Knowlton J, Andrykovitch M, Pei W, Kajava A . Redesign of a four-helix bundle protein by phage display coupled with proteolysis and structural characterization by NMR and X-ray crystallography. J Mol Biol. 2002; 323(2):253-62. DOI: 10.1016/s0022-2836(02)00884-7. View

Palczewski K, Kumasaka T, Hori T, Behnke C, Motoshima H, Fox B . Crystal structure of rhodopsin: A G protein-coupled receptor. Science. 2000; 289(5480):739-45. DOI: 10.1126/science.289.5480.739. View

Hanson M, Cherezov V, Griffith M, Roth C, Jaakola V, Chien E . A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure. 2008; 16(6):897-905. PMC: 2601552. DOI: 10.1016/j.str.2008.05.001. View

Panula P, Chazot P, Cowart M, Gutzmer R, Leurs R, Liu W . International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors. Pharmacol Rev. 2015; 67(3):601-55. PMC: 4485016. DOI: 10.1124/pr.114.010249. View

Zhang Y, Sun B, Feng D, Hu H, Chu M, Qu Q . Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature. 2017; 546(7657):248-253. PMC: 5587415. DOI: 10.1038/nature22394. View

Arrang J, Garbarg M, Schwartz J . Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor. Nature. 1983; 302(5911):832-7. DOI: 10.1038/302832a0. View

10.

Toyoda Y, Morimoto K, Suno R, Horita S, Yamashita K, Hirata K . Ligand binding to human prostaglandin E receptor EP at the lipid-bilayer interface. Nat Chem Biol. 2018; 15(1):18-26. DOI: 10.1038/s41589-018-0131-3. View

11.

Haas H, Sergeeva O, Selbach O . Histamine in the nervous system. Physiol Rev. 2008; 88(3):1183-241. DOI: 10.1152/physrev.00043.2007. View

12.

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

13.

Song G, Yang D, Wang Y, de Graaf C, Zhou Q, Jiang S . Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature. 2017; 546(7657):312-315. DOI: 10.1038/nature22378. View

14.

Berlin M, Boyce C, de Lera Ruiz M . Histamine H3 receptor as a drug discovery target. J Med Chem. 2010; 54(1):26-53. DOI: 10.1021/jm100064d. View

15.

Qu L, Zhou Q, Xu Y, Guo Y, Chen X, Yao D . Structural Basis of the Diversity of Adrenergic Receptors. Cell Rep. 2019; 29(10):2929-2935.e4. DOI: 10.1016/j.celrep.2019.10.088. View

16.

Michino M, Beuming T, Donthamsetti P, Newman A, Javitch J, Shi L . What can crystal structures of aminergic receptors tell us about designing subtype-selective ligands?. Pharmacol Rev. 2014; 67(1):198-213. PMC: 4279073. DOI: 10.1124/pr.114.009944. View

17.

Roth B, Shoham M, Choudhary M, Khan N . Identification of conserved aromatic residues essential for agonist binding and second messenger production at 5-hydroxytryptamine2A receptors. Mol Pharmacol. 1997; 52(2):259-66. DOI: 10.1124/mol.52.2.259. View

18.

Tiligada E, Ennis M . Histamine pharmacology: from Sir Henry Dale to the 21st century. Br J Pharmacol. 2018; 177(3):469-489. PMC: 7012941. DOI: 10.1111/bph.14524. View

19.

Taghon G, Rowe J, Kapolka N, Isom D . Predictable cholesterol binding sites in GPCRs lack consensus motifs. Structure. 2021; 29(5):499-506.e3. PMC: 9162085. DOI: 10.1016/j.str.2021.01.004. View

20.

Leurs R, Vischer H, Wijtmans M, de Esch I . En route to new blockbuster anti-histamines: surveying the offspring of the expanding histamine receptor family. Trends Pharmacol Sci. 2011; 32(4):250-7. DOI: 10.1016/j.tips.2011.02.004. View