MP

Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity.

Lazarova M, Eicher T, Börnsen C, Zeng H, Athar M, Okada U, Yamashita E, Spannaus IM, Borgosch M, Cha HJ, Vargiu AV, Murakami S, Diederichs K, Frangakis AS, Pos KM.

Nat Commun. 2025 Nov 26;16(1):11649. 

doi: 10.1038/s41467-025-66751-3.

PMID: 41298458.

RND efflux pumps substrate specificity varies across phylogenetic clusters. Here:  transferring a single conserved residue between the AcrB and OqxB clusters alters the physicochemical properties of the binding pocket but also the conformational equilibrium of the transport cycle. 

Cryo-EM analysis => AcrB and OqxB adopt fundamentally different apo states => distinct mechanisms for initial substrate binding. 

Cryo-EM analysis of the Staphylococcus aureus phenol-soluble modulin exporter PmtCD apo form in detergent micelles, nanodiscs and peptidiscs. 

Hu J, Lazarski AC, Li FKK, Worrall LJ, Burgin DJ, Zeytuni N, Dickey SW, Otto M, Strynadka NCJ.

Commun Biol. 2025 Nov 17;8(1):1576. 

doi: 10.1038/s42003-025-08955-3. 

PMID: 41249510.

PmtCD exporter in Staphylococcus aureus => secretion of phenol-soluble modulins (key virulence factors). 

cryo-EM => apo form of PmtCD in detergent micelles, NDs, and peptidiscs.

=> its conformation varies depending on the membrane-mimetic environment. 

Structural elucidation of the hexameric MmpS4-MmpL4 complex from Mycobacterium tuberculosis.

Jennifer C Earp, Nicolas P Lichti, Alisa Garaeva, Virginia Meikle, Michael Niederweis, Markus A Seeger

bioRxiv 2026.01.07.698164; 

doi: https://doi.org/10.64898/2026.01.07.698164.

MmpS4-MmpL4 complex in M. tuberculosis = essential for exporting mycobactin and the anti-TB drug bedaquiline. 

Here : cryo-EM and AF-guided disulfide cross-linking to determine the structure of the hexameric (MmpS4)₃-(MmpL4)₃ complex. 

=> coiled-coil domain protruding into the periplasm and a large periplasmic + rearrangements of proton-coupling residues in the TM domain. 

Structure and mechanism of plant urea transporter DUR3.

Wang Y, Green MN, Lin H, Sander AM, Mazurek C, Lin X, Li T, Wang R, Li W, Davis GV, Zhao X, Zhu L, Feng P, Frommer WB, Zhang J, Wudick MM, Fan M.

New Phytol. 2025 Nov 19. 

doi: 10.1111/nph.70752. Online ahead of print.

PMID: 41261797.

DUR3 = plant urea transporter that plays a critical role in nitrogen uptake and recycling. 

cryo-EM and functional assays => structure of DUR3, unique transport mechanism involving conformational changes in its transmembrane helices. 

Identification of key residues that mediate urea selective binding and translocation 

Structural determination of the human taurine transporter TauT reveals the mechanism of substrate and inhibitor recognition.

Lu Y, Ding D, Chen H, Jiang P, Luo J, Shan H, Wang G, Luo J, Yin Y.

Cell Rep. 2025 Dec 23;44(12):116591. 

doi: 10.1016/j.celrep.2025.116591. Epub 2025 Nov 19.

PMID: 41269860.     

Human taurine transporter TauT = vital for maintaining cellular taurine levels, (osmoregulation and antioxidant defense). 

cryo-EM structure of TauT => substrate-binding site and conformational changes that facilitate taurine transport. 

Identification how inhibitors bind to TauT = structural basis for designing drugs that modulate its activity.

Stereochemical insight for MexXY-OprM efflux system inhibition in Pseudomonas aeruginosa from a pool of dihydro and tetrahydro berberine derivatives.

Tosiani VD, Di Gregorio A, Giorgini G, Vignaroli C, Mari G, Mantellini F, Favi G, Minnelli C, Mobbili G, Simoni S, Galeazzi R.

Chem Biol Interact. 2026 Jan 25;424:111850. 

doi: 10.1016/j.cbi.2025.111850. Epub 2025 Nov 28.

PMID: 41319800.     

Exploration of the inhibitory potential of dihydro and tetrahydro berberine derivatives => stereochemistry affects binding to the MexXY-OprM complex. 

Molecular docking + functional assays => specific derivatives that effectively block efflux activity. 

Doxorubicin recognition and transport by the MATE multidrug transporter NorM from Vibrio cholerae.

Hsieh PY, Romane K, Kowal J, Locher KP, van Veen HW.

J Mol Biol. 2025 Nov 17:169549. 

doi: 10.1016/j.jmb.2025.169549. Online ahead of print.

PMID: 41260293.

NorM, MATE from Vibrio cholerae, confers resistance to a broad range of antibiotics, including doxorubicin. 

Cryo-EM + biochemical assays => NorM recognizes and transports doxorubicin, highlighting key residues in the binding pocket. 

NorM undergoes conformational changes to accommodate doxorubicin, which is then extruded via a proton-coupled mechanism.

Conduction pathway for potassium through the Escherichia coli pump KdpFABC.

Hussein A, Zhang X, Pedersen BP, Stokes DL.

Elife. 2025 Nov 19;14:RP107397. 

doi: 10.7554/eLife.107397.

PMID: 41259220.   

KdpFABC complex in E. coli = high-affinity potassium pump essential for bacterial survival under low-potassium conditions. 

Here: cryo-EM and electrophysiology to map the potassium conduction pathway through KdpFABC, revealing a series of coordinated conformational changes that facilitate ion transport. 

Critical residues lining the conduction pathway are conserved across bacterial species.

Structural basis of vilazodone dual binding mode to the serotonin transporter.

Kalenderoglou IE, Nygaard A, Vogt CD, Turaev A, Pape T, Adams NBP, Newman AH, Loland CJ.

Nat Commun. 2025 Nov 18;16(1):10119. 

doi: 10.1038/s41467-025-65202-3.

PMID: 41253806   

Vilazodone = unique antidepressant => acts as both a serotonin reuptake inhibitor and a 5-HT1A receptor partial agonist. 

Here: cryo-EM structure of vilazodone bound to the human serotonin transporter (SERT), revealing a dual binding mode that explains its pharmacological profile. 

Vilazodone stabilizes SERT in a conformation that blocks serotonin transport while simultaneously activating 5-HT1A signaling. 

Structures of human organellar SPFH protein complexes.

Gao J, Sherpa D, Kupko N, Chino H, Zeng J, Shao S.

Nat Commun. 2025 Nov 17;16(1):10064. 

doi: 10.1038/s41467-025-65078-3.

PMID: 41249155.     

SPFH (stomatin, prohibitin, flotillin, and HflK/C) = scaffolding protein complexes involved in membrane organization and signaling. 

Here : structures of human organellar SPFH complexes.

=> they assemble into higher-order oligomers to modulate membrane curvature and protein-lipid interactions. 

=> mutations disrupting SPFH complex formation are linked to neurological and metabolic disorders.

Biophysical and immunoinformatics insights into TolC, an outer membrane multidrug efflux channel of Vibrio cholerae.

Singh B, Kodgire P.

J Biomol Struct Dyn. 2025 Nov 18:1-15. 

doi: 10.1080/07391102.2025.2589330. Online ahead of print.

PMID: 41252541.

Biophysical simulations and immunoinformatics to characterize structure and dynamics of TolC from Vibrio cholerae.

=> key regions that interact with efflux pump partners and substrates. 

=> model how TolC conformational flexibility enables export of diverse compounds.

Membranes

Coadministration of a crystalline drug compromises supersaturation and membrane transport of an amorphous drug.

Alkalla N, Alhalaweh A, Bergström CAS, Li N, Taylor LS.

Int J Pharm. 2025 Nov 13:126388. 

doi: 10.1016/j.ijpharm.2025.126388. Online ahead of print.

PMID: 41241164.

Amorphous drugs often exhibit enhanced solubility and bioavailability (versus crystalline counterparts), but their performance can be compromised by coadministered crystalline drugs. 

Here : crystalline drugs reduce the supersaturation and membrane transport of amorphous drugs, likely through competitive inhibition or precipitation => in vitro models to quantify these effects (importance of formulation strategies to mitigate drug-drug interactions).

Allosteric regulation of BH3-in-groove interactions by tail anchors of BCL-xL complexes limits BH3 mimetic antagonism. 

Maillet L, Fétiveau A, Lalier L, Martin N, Barillé-Nion S, Guette C, Gautier F, Téletchéa S, Juin PP.

Nat Commun. 2025 Nov 22;16(1):10621. 

doi: 10.1038/s41467-025-65509-1. 

PMID: 41274891.

BCL-xL = pro-survival protein that regulates apoptosis by binding to BH3-only proteins via its hydrophobic groove. This study reveals how the tail anchor of BCL-xL allosterically modulates its BH3-binding groove, limiting the efficacy of BH3 mimetic drugs. Using structural and biochemical approaches, the authors show that tail anchor-mediated conformational changes reduce drug binding affinity. These insights provide a mechanistic basis for overcoming resistance to BH3 mimetics in cancer therapy.

The structure of the bacterial outer membrane transporter FusA enabled by addition of the native lipid lipopolysaccharide. 

Machin JM, Mosbahi K, Prakaash D, Radford SE, Walker D, Kalli AC, Ranson NA.

J Struct Biol X. 2025 Nov 18;12:100141. 

doi: 10.1016/j.yjsbx.2025.100141. 

PMID: 41399487.

FusA = outer membrane transporter in Gram-negative bacteria involved in the uptake of iron and other essential nutrients. 

Here : first high-resolution structure of FusA, achieved by incorporating its native LPS into the sample preparation. 

=> LPS stabilizes FusA and facilitates substrate binding.

The configurational length scale in the self-assembly and modulation of higher-order transient protein structures.

Haselwandter CA, MacKinnon R.

Proc Natl Acad Sci U S A. 2025 Nov 25;122(47):e2517902122. 

doi: 10.1073/pnas.2517902122. Epub 2025 Nov 19.

PMID: 41259136.     

Higher-order transient structures (HOTS) = dynamic assemblies of MPs that play critical roles in cellular signaling and organization. 

Here : configurational length scales governing HOTS self-assembly, revealing how weak, reversible interactions drive their formation and modulation. 

=> model for how HOTS achieve functional specificity despite their transient nature, with implications for understanding MP organization.

Intrinsic Asymmetry in Weak Acid Transmembrane Transporters.

Jaeger, Emmi, Sebastian Buss, and Eric Beitz. 2026. 

Biomolecules 16, no. 1: 91. 

https://doi.org/10.3390/biom16010091

Weak acid transmembrane transporters play a crucial role in cellular pH regulation and drug resistance, but their functional asymmetry remains poorly understood. 

Here : intrinsic asymmetry of these transporters => structural and dynamic differences between cytoplasmic and extracellular sides influence substrate binding and translocation. 

The authors use computational modeling and biophysical assays to show that asymmetry in proton coupling and substrate affinity is essential for efficient transport. These findings provide a mechanistic framework for understanding how weak acid transporters contribute to cellular homeostasis and drug efflux.

Structure of HIV-1 Env glycoprotein on virions reveals an alternative fusion subunit organization and native membrane coupling.

Jacob T Croft, Hung N Do, Daniel P Leaman, Klaus N Lovendahl, Pooja Ralli-Jain, Katelyn J Chase, Chengbo Chen, Vidya M Prasad, Cynthia A Derdeyn, Michael B Zwick, S. Gnanakaran, and Kelly K Lee.

bioRxiv posted 10 January 2026. 

doi:10.64898/2026.01.09.698652.

The HIV-1 Env glycoprotein is the primary target for vaccine development, but its native structure on virions has been difficult to characterize. Using cryo-electron tomography and subtomogram averaging, the authors reveal conformational differences in membrane-proximal regions of Env compared to soluble trimers. Hydrogen/deuterium exchange mass spectrometry and molecular dynamics simulations further highlight critical interactions between Env and the viral membrane, showing that membrane disruption relaxes Env into a form resembling engineered, soluble trimers. These results underscore the essential role of the membrane in maintaining Env’s native conformation, offering new insights for vaccine design.

Molecules

Drop Dilution Enables the Use of PEG-Derived Detergents for Membrane Protein Purification.

Katharina Alker, Shweta Singh, Arun K. Vinodakrishnan, Florian Lindemann, Rasmus Linser, Ram Singh, Abhishek K. Singh, Leonhard H. Urner.

ACS Omega 2025, XXXX, XXX, XXX-XXX

https://doi.org/10.1021/acsomega.5c09173

Published November 14, 2025.

PEG-derived detergents are widely used for membrane protein purification but can interfere with downstream applications due to their high viscosity and micelle stability. This study introduces a “drop dilution” method that enables the exchange of PEG-derived detergents into mild, compatible detergents without compromising protein stability. The authors demonstrate the method’s efficacy across multiple membrane proteins, including GPCRs and transporters. This approach expands the toolkit for membrane protein research and drug discovery.

Detergent exchange from lipid nanoparticles into detergent micelles unlocks a tool for biochemical and kinetic characterization of membrane proteins.

Koweek RS, Knox HL, Dodge GJ, Imperiali B, Allen KN.

bioRxiv [Preprint]. 2025 Dec 25:2025.12.23.696072. 

doi: 10.64898/2025.12.23.696072.

PMID: 41509227.     

Lipid nanoparticles (LNPs) are powerful tools for delivering membrane proteins in a native-like environment, but their use in biochemical assays is limited by the presence of lipids. This study describes a method to exchange detergents from LNPs into detergent micelles, enabling the characterization of membrane proteins using standard biochemical and kinetic techniques. The authors validate the method with multiple proteins, including transporters and receptors. This advance could facilitate high-throughput screening and functional studies of membrane proteins.

Methods

Development of an EPR-based methodology to study protein-lipid interaction.

Piersson C, Prakash S, Lublin V, Rossotti M, Fischer B, Srivastava M, Fichou Y.

Biophys Chem. 2025 Nov 8;329:107550. 

doi: 10.1016/j.bpc.2025.107550. Online ahead of print.

PMID: 41259939.

Protein-lipid interactions are essential for membrane protein function but remain challenging to study due to their dynamic and heterogeneous nature. This study introduces an electron paramagnetic resonance (EPR)–based methodology to probe these interactions at the molecular level. The authors demonstrate how EPR spectroscopy can reveal lipid binding sites, conformational changes, and the impact of lipid composition on protein activity. This method provides a powerful tool for understanding membrane protein biology and designing lipid-targeted therapeutics.

Microbio

Evaluating the ciprofloxacin potentiation efficacy of repurposed drug flupentixol through efflux pump inhibition of pathogenic bacteria.

Momin-Reza M, Rafi RH, Mia R, Tawfiq MJ, Khan MRI, Faruqe MO, Ehaimir SY, Al-Bari MAA.

Sci Rep. 2025 Nov 17;15(1):40239. 

doi: 10.1038/s41598-025-24167-5.

PMID: 41249411.    

Efflux pumps are a major contributor to antibiotic resistance in pathogenic bacteria, limiting the efficacy of fluoroquinolones like ciprofloxacin. This study evaluates the potentiation of ciprofloxacin by flupentixol, a repurposed antipsychotic drug, through inhibition of bacterial efflux pumps. The authors show that flupentixol significantly enhances ciprofloxacin activity against multidrug-resistant strains, including E. coli and P. aeruginosa. These results highlight the potential of drug repurposing to combat antibiotic resistance and restore the efficacy of existing antibiotics.

Miscellaneous

A comparative approach to the evolution of kissing

Matilda Brindle, Catherine F. Talbot, Stuart West.

Evolution and Human Behavior. Volume 47, Issue 1, January 2026, 106788.

https://doi.org/10.1016/j.evolhumbehav.2025.106788

Kissing, romantically defined as a ”non-agonistic oral-oral contact without food transfer” (🤣), is observed across primates and likely evolved in the common ancestor of great apes and Neanderthals. 

This behavior correlates with life history traits such as multi-male mating systems, non-folivorous diets, and premastication, though these relationships are not absolute. The study provides a phylogenetic framework for further research into the adaptive functions of kissing, despite current data limitations.

Noncovalent interactions as key modulators of PFAS translocation, lipid-protein affinity, and tissue partitioning.

Tansel B.

J Hazard Mater. 2025 Dec 24;501:140933. 

doi: 10.1016/j.jhazmat.2025.140933. Online ahead of print.

PMID: 41456435.  

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants that accumulate in biological tissues, posing significant health risks. This study investigates how noncovalent interactions—such as hydrogen bonding, hydrophobic effects, and electrostatic forces—govern PFAS translocation across membranes and their affinity for lipid-protein complexes. The authors use computational modeling to identify key molecular features that drive PFAS tissue partitioning. These findings provide a mechanistic understanding of PFAS bioaccumulation and could inform strategies for mitigating their toxic effects.

Introducing the j-metric: a true measure of what matters in academia. 

Jemielniak D. 

Nature. 2025 Dec;648(8092):240-241. 

doi: 10.1038/d41586-025-03349-1. 

PMID: 41254249.

Science has become obsessed with publishing numbers. With this new satirical proposal, have we reached peak metric?

inspiring citations herein :

”metrics are like trying to measure the ocean by counting waves, each new metric promising to quantify them more accurately than the last”.

”“quantitative evaluation should support qualitative, expert assessment” — a bit like reminding people that food should be chewed before swallowing”.

”The result of an obsession with metrics is that we’ve standardized scholarship to the point at which a publication is a publication is a publication, regardless of whether it represents years of archival research or a weekend’s worth of data massage. As academia becomes McDonaldized — subject to the fast-food industry principles of efficiency, calculability, predictability and control — one phrase becomes relevant: ‘Do you want cites with that?’”

”We get what we measure, and what we’re measuring is measuring itself”.