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Membrane Proteins: Structure, Function, and Drug Discovery
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Membrane Proteins: Structure, Function, and Drug Discovery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 May 2025) | Viewed by 6319

Special Issue Editor

Prof. Dr. Masafumi Yohda

E-Mail Website
Guest Editor
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Tokyo 184-8588, Japan
Interests: chaperone; olfaction; structural biology

Special Issue Information

Dear Colleagues,

Membrane protein research is critical for understanding fundamental cellular processes and advancing therapeutic strategies. Membrane proteins, such as receptors, ion channels, and transporters, are essential for a wide range of physiological functions, including signal transduction, nutrient uptake, and the maintenance of cellular homeostasis. When these proteins malfunction, they can contribute to various diseases. As a result, membrane proteins are vital targets for drug discovery, particularly G-protein-coupled receptors (GPCRs) and ion channels, which are central to many modern therapies.

Recent advances in structural biology, including cryo-electron microscopy (cryo-EM) and computational modeling, have significantly enhanced our understanding of the detailed mechanisms underlying membrane protein function. These breakthroughs also facilitate the design of more targeted and effective drugs.

Additionally, understanding how membrane proteins interact with lipids and their surrounding environment is crucial for elucidating their roles in disease and developing more precise therapies.

In summary, research on membrane proteins is foundational to both basic biology and the development of novel medical treatments, with broad implications for human health and disease management.

Prof. Dr. Masafumi Yohda
Guest Editor

Manuscript Submission Information

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Keywords

  • ion channel
  • GPCR (G-protein-coupled receptor)
  • membrane transporters
  • signal transduction
  • membrane lipids
  • cryo-EM (cryo-electron microscopy)
  • membrane protein folding
  • membrane rafts
  • reconstitution

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Published Papers (4 papers)

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Research

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15 pages, 1364 KB  
Article
AT-TSVM: Improving Transmembrane Protein Inter-Helical Residue Contact Prediction Using Active Transfer Transductive Support Vector Machines
by Bander Almalki, Aman Sawhney and Li Liao
Int. J. Mol. Sci. 2025, 26(22), 10972; https://doi.org/10.3390/ijms262210972 - 12 Nov 2025
Viewed by 489
Abstract
Alpha helical transmembrane proteins are a specific type of membrane proteins that consist of helices spanning the entire cell membrane. They make up almost a third of all transmembrane (TM) proteins and play a significant role in various cellular activities. The structural prediction [...] Read more.
Alpha helical transmembrane proteins are a specific type of membrane proteins that consist of helices spanning the entire cell membrane. They make up almost a third of all transmembrane (TM) proteins and play a significant role in various cellular activities. The structural prediction of these proteins is crucial in understanding how they behave inside the cell and thus in identifying their functions. Despite their importance, only a small portion of TM proteins have had their structure determined experimentally. Inter-helical residue contact is one of the most successful computational approaches for reducing the TM protein fold search space and generating an acceptable 3D structure. Most current TM protein residue contact predictors use features extracted only from protein sequences to predict residue contacts. However, these features alone deliver a low-accuracy contact map and, as a result, a poor 3D structure. Although there are models that explore leveraging features extracted from protein 3D structures in order to produce a better representative contact model, such an approach remains theoretical, assuming the structure features are available, whereas in reality they are only available in the training data, but not in the test data, whose structure is what needs to be predicted. This presents a brand new transfer learning paradigm: training examples contain two sets of features, but test examples contain only one set of the less informative features. In this work, we propose a novel approach that can train a model with training examples that contain both sequence features and atomic features and apply the model on the test data that contain only sequence features but not atomic features, while still improving contact prediction rather than using sequence features alone. Specifically, our method, AT-TSVM, employs Active Transfer for Transductive Support Vector Machines, which is augmented with transfer, active learning and conventional transductive learning to enhance contact prediction accuracy. Results from a benchmark dataset show that our method can boost contact prediction accuracy by an average of 5 to 6% over the inductive classifier and 2.5 to 4% over the transductive classifier. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function, and Drug Discovery)
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15 pages, 2067 KB  
Article
Insights into Chemoreceptor MCP2201-Sensing D-Malate
by Rui Cui, Jie Li, Yuan Hong, Lu Guo, Yun-Hao Wang, Yi-Fei Bai and De-Feng Li
Int. J. Mol. Sci. 2025, 26(10), 4902; https://doi.org/10.3390/ijms26104902 - 20 May 2025
Viewed by 822
Abstract
Bacterial chemoreceptors sense extracellular stimuli and drive bacteria toward a beneficial environment or away from harm. Their ligand-binding domains (LBDs) are highly diverse in terms of sequence and structure, and their ligands cover various chemical molecules that could serve as nitrogen, carbon, and [...] Read more.
Bacterial chemoreceptors sense extracellular stimuli and drive bacteria toward a beneficial environment or away from harm. Their ligand-binding domains (LBDs) are highly diverse in terms of sequence and structure, and their ligands cover various chemical molecules that could serve as nitrogen, carbon, and energy sources. The mechanism of how this diverse range of LBDs senses different ligands is essential to signal transduction. Previously, we reported that the chemoreceptor MCP2201 from Comamonas testosteroni CNB-1 sensed citrate and L-malate, altered the ligand-free monomer–dimer equilibrium of LBD to citrate-bound monomer (with limited monomer) and L-malate-bound dimer, and triggered positive and negative chemotactic responses. Here, we present our findings, showing that D-malate binds to MCP2201, induces LBD dimerization, and triggers the chemorepellent response exactly as L-malate did. A single site mutation, T105A, can alter the D-malate-bound LBD dimer into a monomer–dimer equilibrium and switch the negative chemotactic response to D-malate to a positive one. Differences in attractant-bound LBD oligomerization, such as citrate-bound wildtype LBD monomer and D-malate-bound T105A dimer, indicated that LBD oligomerization is a consequence of signal transduction instead of a trigger. Our study expands our knowledge of chemoreceptor-sensing ligands and provides insight into the evolution of bacterial chemoreceptors. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function, and Drug Discovery)
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13 pages, 7585 KB  
Article
Harnessing Odorant Receptor Activation to Suppress Real Malodor
by Reina Kanemaki, Kahori Kishigami, Mei Saito, Masafumi Yohda and Yosuke Fukutani
Int. J. Mol. Sci. 2025, 26(4), 1566; https://doi.org/10.3390/ijms26041566 - 13 Feb 2025
Cited by 1 | Viewed by 2123
Abstract
Mammals, including humans, sense smell by the responses of odorant receptors (ORs) to odor molecules. We have developed an effective method to identify novel antagonists capable of suppressing the pungent odor of cat urine by targeting specific ORs. Since odors are typically complex [...] Read more.
Mammals, including humans, sense smell by the responses of odorant receptors (ORs) to odor molecules. We have developed an effective method to identify novel antagonists capable of suppressing the pungent odor of cat urine by targeting specific ORs. Since odors are typically complex mixtures of multiple volatile compounds, olfactory perception can vary depending on the composition. We analyzed the response of ORs to cat urine odor using vapor stimulation assays to identify the responding ORs. Gas chromatography–mass spectrometry was then performed to identify compounds eliciting responses from these ORs. Trace-amine-associated receptor 5 (TAAR5) demonstrated a significant response associated with the odor intensity of cat urine, identifying trimethylamine as a major contributor to the strong odor. From hundreds of candidate compounds, we identified several novel antagonists that exhibited greater efficacy than a known TAAR5 antagonist. These compounds not only reduced the responses of TAAR5-expressing cells to cat urine odor but also significantly reduced odor intensity and improved sensory pleasantness in human tests. Our findings suggest that targeting ORs responsive to specific odors, without isolating their individual components, is a promising strategy for developing deodorizing agents against complex malodors like cat urine odor. This study emphasizes the value of using real odor mixtures to enhance our understanding of odor perception. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function, and Drug Discovery)
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Review

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46 pages, 9005 KB  
Review
Chemosensory Receptors in Vertebrates: Structure and Computational Modeling Insights
by Aurore Lamy, Rajesh Durairaj and Patrick Pageat
Int. J. Mol. Sci. 2025, 26(14), 6605; https://doi.org/10.3390/ijms26146605 - 10 Jul 2025
Viewed by 2287
Abstract
Chemical communication is based on the release of chemical cues, including odorants, tastants and semiochemicals, which can be perceived by animals and trigger physiological and behavioral responses. These compounds exhibit a wide size and properties range, spanning from small volatile molecules to soluble [...] Read more.
Chemical communication is based on the release of chemical cues, including odorants, tastants and semiochemicals, which can be perceived by animals and trigger physiological and behavioral responses. These compounds exhibit a wide size and properties range, spanning from small volatile molecules to soluble proteins, and are perceived by various chemosensory receptors (CRs). The structure of these receptors is very well conserved across all organisms and within the family to which they belong, the G-protein-coupled receptor (GPCR) family. It is characterized by highly conserved seven-transmembrane (7TM) α-helices. However, the characteristics of these proteins and the methods used to study their structures are limiting factors for resolving their structures. Due to the importance of CRs—especially olfactory and taste receptors, responsible for two of our five basic senses—alternative methods are utilized to overcome these structural challenges. Indeed, in silico structural biology is an expanding field that is very useful for CR structural studies. Since the 1960s, many algorithms have been developed and improved in an attempt to resolve protein structure. We review the current knowledge regarding different vertebrate CRs in this study, with an emphasis on the in silico structural methods employed to improve our understanding of CR structures. Full article
(This article belongs to the Special Issue Membrane Proteins: Structure, Function, and Drug Discovery)
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