Quantitative Deciphering of Mammalian Histamine Receptors through Mathematical Genomics
Open accessPreprint — published as 10.1016/j.bbrc.2026.153717 · Paper page
Abstract
Histamine receptors (HRH1–HRH4) are G-protein coupled receptors (GPCRs) that mediate essential physiological functions, including neurotransmission, gastric acid secretion, immune regulation, and presynaptic autoregulation. Despite their importance, systematic comparative analyses across mammalian histamine receptor sequences remain scarce. In this study, we performed a comprehensive evaluation of HRH1–HRH4 across multiple mammalian species, integrating sequence homology, invariant residue mapping, amino acid substitutions, compositional frequencies, Shannon entropy, polystring distributions, intrinsic disorder profiling, and phylogenetic clustering. HRH2 and HRH1 were highly conserved among primates, HRH3 showed strong cohesion within rodents, while HRH4 exhibited pronounced divergence consistent with immune-related specialization. Invariant residues localized to transmembrane helices and activation motifs (D107, W428/Y431, NPxxY), underscoring strict evolutionary constraints on ligand binding, receptor stability, and G-protein coupling. Substitutions were confined to non-essential lipid-facing and loop regions, predominantly conservative in nature, enabling diversification without disrupting the GPCR fold. Amino acid frequency and entropy analyses revealed hydrophobic dominance with subtype-specific enrichment of polar residues, while disorder profiling identified HRH1 as the most dynamic and HRH2 as the most structurally constrained. Polystring analysis highlighted conserved motifs (WWW, PP) alongside subtype- and species-specific repeats, reflecting evolutionary strategies balancing receptor stability with adaptive flexibility. Phylogenetic clustering confirmed subtype-specific cohesion, with HRH3 and HRH4 forming compact clades, HRH1 showing moderate dispersion, and HRH2 forming the most isolated cluster. Collectively, these findings demonstrate that mammalian histamine receptor evolution is governed by conserved biophysical cores and selective variability, offering insights into structural conservation, functional diversification, and translational relevance for drug design and model selection.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
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Research works printed but not linked: 59
- 1996, Immunopharmacology Reviews, 2, 261
- 1959, A method for the fluorometric assay of histamine in tissues, The Journal of Pharmacology and Experimental Therapeutics, 127, 182, 10.1016/S0022-3565(25)25681-6 · DOI
- 10.1038/nrn3526 · DOI
- 2022, Histamine: a mediator of intestinal disorders—a review, Metabolites, 12, 895, 10.3390/metabo12100895 · DOI
- 10.1074/jbc.M006480200 · DOI
- 10.1016/j.ejphar.2005.12.044 · DOI
- 10.1038/sj.bjp.0706704 · DOI
- 10.1073/pnas.81.8.2572 · DOI
- 10.1111/bph.13878 · DOI · Paper page
- 2011, The basics of histamine biology, Annals of Allergy, Asthma & Immunology, 106, S2, 10.1016/j.anai.2010.08.005 · DOI
- 10.1007/s12026-008-8050-0 · DOI
- 2017, Visualizing the gpcr network: classification and evolution, Scientific reports, 7, 15495, 10.1038/s41598-017-15707-9 · DOI
- 2009, Signaling through g protein coupled receptors, Plant signaling & behavior, 4, 942, 10.4161/psb.4.10.9530 · DOI
- 10.1016/S0165-6147(00)01678-3 · DOI · Paper page
- 10.1074/jbc.273.4.1839 · DOI · Paper page
- R. A. Bakker , H. Timmerman , R. Leurs , Histamine receptors: Specific ligands, receptor biochemistry, and signal transduction, Histamine and H1-antihistamines in allergic disease (2002) 43–80. · DOI
- 10.1038/nrd1631 · DOI
- 10.1016/j.tips.2005.07.002 · DOI
- 2001, Comparison of human, mouse, rat, and guinea pig histamine h4 receptors reveals substantial pharmacological species variation, The Journal of pharmacology and experimental therapeutics, 299, 121, 10.1016/S0022-3565(24)29309-5 · DOI
- 2002, , cdna cloning and characterization of porcine histamine h4 receptor, Biochimica et Biophysica Acta (BBA)-Gene Structure and Expression, 1575, 135, 10.1016/S0167-4781(02)00236-1 · DOI
- 10.1254/jphs.SC0050033 · DOI
- 2021, Evolutionary history of histamine receptors: Early vertebrate origin and expansion of the h3-h4 subtypes, Molecular Phylogenetics and Evolution, 154, 106989, 10.1016/j.ympev.2020.106989 · DOI
- 10.1111/j.1476-5381.2009.00151.x · DOI
- 2015, The histamine h4 receptor: from orphan to the clinic, Frontiers in Pharmacology, 6, 65
- 10.1093/nar/gkae1010 · DOI · Paper page
- 10.1038/msb.2011.75 · DOI
- 2014, Clustal omega, Current protocols in bioinformatics, 48, 3
- 10.1002/PRO.3290 · DOI · Paper page
- F. Sievers , D. G. Higgins , The clustal omega multiple alignment package, in: Multiple sequence alignment: Methods and protocols, Springer, 2020, pp. 3–16. · DOI
- 2002, A genetic algorithm for the identification of conformationally invariant regions in protein molecules, Biological Crystallography, 58, 195, 10.1107/S0907444901019291 · DOI
- 1966, The amino acid composition of proteins, Journal of Theoretical Biology, 13, 261, 10.1016/0022-5193(66)90021-X · DOI
- 10.1534/genetics.104.039107 · DOI
- S. S. Hassan , D. Nawn , A. Ghosh , M. Sil , A. Goswami , P. Basu , K. Lundstrom , V. N. Uversky , Methuselah proteins in drosophila: Structural and evolutionary insights from mathematical genomics, Biochemical and Biophysical Research Communications (2025) 152240. · DOI
- 1973, A statistical analysis of the amino acid compositions of proteins, International Journal of Peptide and Protein Research, 5, 109, 10.1111/j.1399-3011.1973.tb02325.x · DOI
- 10.1016/S0006-3495(96)79210-X · DOI
- 2002, Entropy of protein sequences: an integral approach, Journal of Biomolecular Structure and Dynamics, 20, 87, 10.1080/07391102.2002.10506825 · DOI
- 1974, Entropy increase of amino acid sequence in protein, Journal of Molecular Evolution, 4, 179, 10.1007/BF01732022 · DOI
- 2010, Relative von neumann entropy for evaluating amino acid conservation, Journal of bioinformatics and computational biology, 8, 809, 10.1142/S021972001000494X · DOI
- 2024, Unveiling the genetic tapestry: Rare disease genomics of spinal muscular atrophy and phenylketonuria proteins, International Journal of Biological Macromolecules, 269, 131960, 10.1016/j.ijbiomac.2024.131960 · DOI
- D. Nawn , S. S. Hassan , A. Hromić-Jahjefendić , T. Bhattacharya , P. Basu , E. M. Redwan , D. Barh , B. S. Andrade , A. A. Aljabali , Á. Serrano-Aroca , et al., Molecular genomic insights into melanoma associated proteins prame and bap1, Journal of Biomolecular Structure and Dynamics (2025) 1–31. · DOI · Paper page
- 10.1002/pro.4496 · DOI
- 2023, Rapid prediction and analysis of protein intrinsic disorder, Biophysical Journal, 122, 61a, 10.1016/j.bpj.2022.11.536 · DOI
- 10.3390/life14101307 · DOI
- 2024, Exploring intrinsic disorder in human synucleins and associated proteins, International Journal of Molecular Sciences, 25, 8399, 10.3390/ijms25158399 · DOI
- 10.1007/s10930-024-10214-z · DOI
- 2025, Genomic perspective on sociosexual behavior: Quantitative analysis of receptor sequences in vertebrates, Next Research, 2, 100247, 10.1016/j.nexres.2025.100247 · DOI
- 2025, Proximal relationships of moonlighting proteins in escherichia coli: A mathematical genomics perspective, International Journal of Biological Macromolecules, 308, 142766, 10.1016/j.ijbiomac.2025.142766 · DOI
- 10.1146/annurev-pharmtox-032112-135923 · DOI
- 10.1038/nature11896 · DOI
- 10.1038/nature10236 · DOI
- 10.1006/bbrc.1994.2295 · DOI
- 2024, G protein-coupled receptors (gpcrs): advances in structures, mechanisms and drug discovery, Signal transduction and targeted therapy, 9, 88, 10.1038/s41392-024-01803-6 · DOI
- 10.1038/nature09648 · DOI
- 2021, Cryo-em structure of the human histamine h1 receptor/gq complex, Nature communications, 12, 2086, 10.1038/s41467-021-22427-2 · DOI
- 2019, Multi-functionality of proteins involved in gpcr and g protein signaling: making sense of structure–function continuum with intrinsic disorder-based proteoforms, Cellular and Molecular Life Sciences, 76, 4461, 10.1007/s00018-019-03276-1 · DOI · Paper page
- 10.1038/nature08144 · DOI · Paper page
- 10.2174/1381612811319230005 · DOI
- 10.1038/nrm3920 · DOI
- 10.1002/j.1460-2075.1986.tb04288.x · DOI · Paper page
- Authors
- Hassan, S. S., Nawn, D., Goswami, P., Mukherjee, N., Sil, M., Roy, S., Goswami, A., Das, S., & Uversky, V. N.
- Affiliations
- Department of Mathematics, Pingla Thana Mahavidyalaya, Maligram, Pingla, 721140, West Bengal, India
- Adamas University (IN)
- DAC Regional Research Institute for Homoeopathy, Kolkata, West Bengal, 700035, India
- Jangipur College (IN)
- Indian Statistical Institute (IN)
- Peerless Hospital & B.K.Roy Research Centre (IN)
- University of South Florida (US)
- Corresponding author
- Uversky, Vladimir N.
- ORCID
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- openRxiv
- Published
- 2026-01-12
- Volume
- 817
- Pages
- 153717-153717
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W7149623792
- Cited by
- 0
- References
- 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- histamine receptors, G protein-coupled receptors, sequence conservation, invariant residues, amino acid substitutions, intrinsic disorder, phylogenetic clustering, Shannon entropy
- MeSH terms
- Receptors, Histamine H4, Amino Acid Sequence, Animals, Humans, Mammals, Phylogeny, Receptors, Histamine, Evolution, Molecular, Genomics, Receptors, G-Protein-Coupled
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