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Quantitative deciphering of mammalian histamine receptors through mathematical genomics

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Hassan, Sk. Sarif, Nawn, Debaleena, Goswami, Pritam, Mukherjee, Nabanita, Sil, Moumita, Roy, Sujan, Goswami, Arunava, Das, Satadal, Uversky, Vladimir N.·2026·Biochemical and Biophysical Research Communications
DOI 10.1016/j.bbrc.2026.153717

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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. The central focus of this study lies in the characterization of both structural features and evolutionary trajectories of histamine receptors, providing a unified perspective on their conservation and diversification. 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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Metadata

Authors
Hassan, S. S., Nawn, D., Goswami, P., Mukherjee, N., Sil, M., Roy, S., Goswami, A., Das, S., & Uversky, V. N.
Affiliations
  • Adamas University (IN)
  • 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
Elsevier BV
Published
2026-06
Volume
817
Pages
153717
ISSN
0006-291X (ISSN-L)
DOI
10.1016/j.bbrc.2026.153717
OpenAlex
W7149623792
Cited by
0
References
1
FWCI
0.00
Type
journal article
Language
en
Open access
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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