MP
Bidirectional communication between nucleotide and substrate binding sites in a type IV multidrug ABC transporter
Victor Hugo Pérez Carrillo, Margot Di Cesare, Dania Rose-Sperling, Waqas Javed, Hannes Neuweiler, Julien Marcoux, Cédric Orelle, Jean-Michel Jault, Ute A. Hellmich
bioRxiv 2025.01.15.633140;
doi: https://doi.org/10.1101/2025.01.15.633140
Type IV ABC transporters rely on coupling helices to connect NBDs and TMDs.
Here:identification of a conserved residue cluster at the NBD/TMD interface in BmrA, essential for relaying nucleotide and substrate binding via coupling helix 2: novel interdomain communication pathway !
Protein-Protein Interaction and Conformational Change in the Alpha-Helical Membrane Transporter BtuCD-F in the Native Cellular Envelope.
Joseph B.Chembiochem. 2025 Jan 226(1):e202400858.
doi: 10.1002/cbic.202400858. Epub 2024 Nov 28.
PMID: 39551706.
Pulsed dipolar electron spin resonance spectroscopy (Gd³⁺-nitroxide spin pairs) to study BtuCD-F in its native cellular envelope => vitamin B12-induced conformational shift at the BtuCD-BtuF interface not observed in micelles.
Two stages of substrate discrimination dictate selectivity in the E. coli MetNI-Q ABC transporter system.
Janet G Yang, Hulda Yuchun Chen, John H Guardado, Maile Gardner, and Matthew S Foronda.
bioRxiv posted 21 January 2025.
doi:10.1101/2025.01.20.633972.
MetNI-Q (ABC transporter in E. coli) selectively imports methionine with a strong preference for L-Met over D-Met (1,000-fold specificity for L-Met) driven primarily by the MetQ substrate binding protein.
This selectivity is further enhanced by differences in binding affinities and release rates enabling faster transport of L-Met compared to D-Met.
=> MetNI-Q = two-step mechanism to optimize methionine uptake based on substrate chirality and availability.
Mg2+-dependent mechanism of environmental versatility in a multidrug efflux pump.
Russell Lewis B, Uddin MR, Kuo KM, Shah LMN, Harris NJ, Booth PJ, Hammerschmid D, Gumbart JC, Zgurskaya HI, Reading E.
Structure. 2025 Jan 10:S0969-2126(24)00547-1.
doi: 10.1016/j.str.2024.12.012. Epub ahead of print.
PMID: 39809273.
In AcrAB-TolC, structural dynamics of AcrA is modulated by Mg²⁺ and pH.
Without Mg²⁺, acidic conditions increase AcrA’s plasticity, while Mg²⁺ binding organizes specific domains and maintains pump activity across pH ranges via a critical histidine residue.
=> This mechanism ensures AcrAB-TolC function in dynamic environments, aiding bacterial survival during infection and colonization.
Multidrug efflux pumps of Pseudomonas aeruginosa show selectivity for their natural substrates.
Mazza Léna, Bory Alexandre, Luscher Alexandre, Kloehn Joachim, Wolfender Jean-Luc, van Delden Christian, Köhler Thilo.
Front. Microbiol., 09 January 2025. Sec. Antimicrobials, Resistance and Chemotherapy.
Volume 15 – 2024 | https://doi.org/10.3389/fmicb.2024.1512472.
Metabolomic approach with mutants lacking specific Mex efflux pumps.
=> identification of 210 pump-specific substrates, including quorum-sensing molecules and secondary metabolite by-products.
Computational assessment and in vitro test of phytochemicals of Usnea aciculifera as potential inhibitors of Escherichia coli efflux pump AcrB.
Phan TV, Tuong LT, Nguyen VT, Vo CT, Tran TD, Le MT, Nguyen BGD, Tran VT, Vu TT, Thai KM.
J Biomol Struct Dyn. 2025 Feb;43(3):1316-1328.
doi: 10.1080/07391102.2023.2291547. Epub 2023 Dec 13.
PMID: 38088368.
Lichens produce secondary metabolites with various pharmaceutical activities.
Twelve phytochemicals were evaluated for AcrAB-TolC efflux pump inhibition, with compound 8 showing significant in vitro activity by enhancing levofloxacin efficacy and forming a stable complex with the AcrB distal pocket.
Molecular docking, dynamics simulations, and ADMET predictions highlight compound 8 as a promising candidate for drug development targeting efflux pump-mediated antibiotic resistance.
Identification of ABC transporter Cdr1 inhibitors of Candida glabrata.
Waseem M Das S Mondal D Kumari A Kulshreshtha R Thakur JK Subbarao N.
Arch Biochem Biophys. 2025 Feb764:110270.
doi: 10.1016/j.abb.2024.110270. Epub 2024 Dec 15.
PMID: 39681305.
HT virtual screening => identification of pentagalloyl glucose as a promising inhibitor of the Candida glabrata Cdr1 transporter.
MD confirms stable binding to CgCdr1.
The structure and function of the ghrelin receptor coding for drug actions.
Shiimura Y Im D Tany R Asada H Kise R Kurumiya E Wakasugi-Masuho H Yasuda S Matsui K Kishikawa JI Kato T Murata T Kojima M Iwata S Masuho I.
Nat Struct Mol Biol. 2025 Jan 20.
doi: 10.1038/s41594-024-01481-6. Online ahead of print.
PMID: 39833471.
Drugs targeting the ghrelin receptor show promise for treating anorexia, obesity, and diabetes, but development is challenging.
Here: cruyEM grehlin structure with anamorelin, showing how different ligands bind to induce distinct conformations and biased signaling.
Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution.
Miyata Y Takahashi K Lee Y Sultan CS Kuribayashi R Takahashi M Hata K Bamba T Izumi Y Liu K Uemura T Nomura N Iwata S Nagata S Nishizawa T Segawa K.
Nat Struct Mol Biol. 2025 Jan32(1):185-198.
doi: 10.1038/s41594-024-01411-6. Epub 2024 Oct 18.
PMID: 39424995.
TMEM63B = membrane structure-responsive lipid scramblase that regulates this distribution by activating bidirectional lipid translocation in response to changes in membrane curvature and thickness.
Here: cryoEM structures of TMEM63B => lipid translocation pathway.
Structural basis for lipid transfer by the ATG2A-ATG9A complex.
Wang Y Dahmane S Ti R Mai X Zhu L Carlson LA Stjepanovic G.
Nat Struct Mol Biol. 2025 Jan32(1):35-47.
doi: 10.1038/s41594-024-01376-6. Epub 2024 Aug 22.
PMID: 39174844
Autophagosomes formation => ATG2A and ATG9A play critical roles in lipid transfer and membrane re-equilibration.
Here: cryoEM structures of human ATG2A in complex with phosphoinositides 4 and ATG9A, showing how ATG9A aligns its lateral pore with ATG2A’s lipid transfer cavity to enable lipid extraction.
Membranes
Review on bacterial outer membrane vesicles: structure vesicle formation separation and biotechnological applications.
Zhao X Wei Y Bu Y Ren X Dong Z.
Microb Cell Fact. 2025 Jan 2124(1):27.
doi: 10.1186/s12934-025-02653-9.
PMID: 39833809.
Review on recent advancements in OMV research (comprehensive overview of their structure, biogenesis, and mechanisms of vesicle formation) + role in pathogenicity and the techniques for their enrichment and isolation + applications of OMVs in the field of biomedicine (diagnostic tools, vaccine candidates, and drug delivery vectors).
Phospholipid Transport Across the Bacterial Periplasm Through the Envelope-spanning Bridge YhdP.
Cooper BF Clark R Kudhail A Dunn D Tian Q Bhabha G Ekiert DC Khalid S Isom GL.
J Mol Biol. 2025 Jan 15437(2):168891.
doi: 10.1016/j.jmb.2024.168891. Epub 2024 Dec 6.
PMID: 39638236
Gram-negative bacteria OM require transport of phospholipids across the cell envelope.
Here: YhdP = key protein, forms an elongated structure with a hydrophobic groove, enabling it to span the bacterial envelope and facilitate phospholipid transport.
MD / crosslinking / bacterial assays => YhdP interacts with phosphate-containing substrates, supporting its role in bridging the cell envelope for efficient lipid trafficking.
Steroids and steroid-like compounds alter the ion permeability of phospholipid bilayers via distinct interactions with lipids and interfacial water.
Larder M, Crowley J, Hossain SI, Deplazes E.
Phys Chem Chem Phys. 2025 Jan 7.
doi: 10.1039/d4cp03254c. Epub ahead of print.
PMID: 39764716.
Using electrical impedance spectroscopy and molecular dynamics simulations => steroids like cortisone, prednisolone, progesterone, and steroid-like compounds (enoxolone and carbenoxolone) increase membrane permeability by thinning the bilayer and reducing lipid order.
Also show that steroid-like compounds disrupt membranes through hydrogen-bonding interactions.
Viroporins: discovery methods of study and mechanisms of host-membrane permeabilization.
Alcaraz A Nieva JL.Q Rev Biophys. 2025 Jan 1458:e1.
doi: 10.1017/S0033583524000192.
PMID: 39806799
Viroporins = small, integral MPs encoded by viruses that form transmembrane channels during viral replication, influencing virion assembly, release, and cell physiology.
Despite their structural diversity, they function as ion or solute transporters (proton transporters, pores facilitating metabolite diffusion, …).
Here: review exploring the origin, evolution, and structural characterization of viroporins + role in virus production and potential use in live attenuated vaccines.
Depth-Resolved Temperature-Dependent Penetration of Polymyxin B in Phospholipids/Lipopolysaccharide Asymmetric Bilayers
N Paracini, JH Lakey, LA Clifton
ACS Omega, 2025
https://pubs.acs.org/doi/full/10.1021/acsomega.4c07648
Polymyxin B (PmB) = last-resort antibiotic, disrupts the LPS layer’s stability.
Here: fully deuterated OM models to track PmB penetration through neutron reflectometry.
=> PmB accumulates primarily in the hydrophobic region of lipid A, hijacking LPS molecules and penetrating the membrane in a temperature- and concentration-dependent manner.
Phototriggered proton-selective carrier currents through photoswitchable membranes
Juergen Pfeffermann, Rohit Yadav, Toma Glasnov, Oliver Thorn-Seshold, Peter Pohl
bioRxiv 2025.01.13.632814;
doi: https://doi.org/10.1101/2025.01.13.632814
Combination of small-molecule carriers with azobenzene-containing photolipids to achieve rapid and reversible ion-selective permeability modulation by light.
=> rapid, non-invasive, spatially precise, and reversible light-triggered currents can be achieved without genetic modifications.
Molecules
Impact of fluorination on membrane-protein stabilization and extraction by lactobionamide detergents.
Durand G, Cornut D, Soulié M, Moreno A, Guillet P, Keller S, Mahler F, Onyia K.
Chempluschem. 2025 Jan 15:e202400740.
doi: 10.1002/cplu.202400740. Epub ahead of print.
PMID: 39812556.
New detergents with a lactobionamide polar head and perfluorinated carbon tails. CMC decrease significantly as the chain length increases.
DLS => the hydrodynamic diameter of these detergents increases with chain length, while solubilization and stabilization vary across different derivatives.
Perfluorohexyl derivative excels in solubilization, and the perfluoropentyl derivative in stabilization.
Methods
Membrane Proteins in Nanodiscs: Methods and Applications.
Guo J, Hou Q, Tan Y, Fu R, Huang X, Cao C.
ChemMedChem. 2025 Jan 18:e202400775.
doi: 10.1002/cmdc.202400775. Epub ahead of print.
PMID: 39825697.
Review outlining the advancements in ND and applications from 2018 to 2024: development of various nanodisc models, as well as structural and functional studies of membrane proteins that utilize nanodiscs, highlighting their medical applications.
Rapid microfluidic perfusion system enables controlling dynamics of intracellular pH regulated by Na+/H+ exchanger NHE1.
Tran QD Bouret Y Noblin X Jarretou G Counillon L Poët M Cohen C.
Lab Chip. 2025 Jan 13.
doi: 10.1039/d4lc00884g. Online ahead of print.
PMID: 39803906.
New microfluidic system to precisely control ionic chemical species flow, enabling intracellular pH regulation mechanisms in real-time !
Tracking of intracellular pH dynamics and description of varying pH recovery behaviors by use of pH-sensitive fluorescence imaging and a mathematical model.
Split Membrane: A New Model to Accelerate All-Atom MD Simulation of Phospholipid Bilayers.
Hazrati MK, Sukeník L, Vácha R.
J Chem Inf Model. 2025 Jan 8.
doi: 10.1021/acs.jcim.4c01664. Epub ahead of print.
PMID: 39779296.
New all-atom MD model that accelerates lipid diffusion by splitting phospholipids into head and tail groups, maintaining bilayer structure through external lateral potentials.
=> enhances lipid diffusion > 10x => faster and more cost-effective equilibration of large systems with different phospholipids.
In situ light-driven pH modulation for NMR studies
Aarav Barde, Ruixian Han, Martin A. Olson, Marco Tonelli, Chad M. Rienstra, Katherine Henzler-Wildman, Thirupathi Ravula
bioRxiv 2025.01.16.633412; doi: https://doi.org/10.1101/2025.01.16.633412
Novel approach to control pH in NMR samples using light-activated photoacids (ability to precisely modulate pH without physically manipulating the sample). This method enables non-invasive pH titration in NMR studies, where pH plays a key role in protein function.
Cryo-electron tomography pipeline for plasma membranes.
Sun WW Michalak DJ Sochacki KA Kunamaneni P Alfonzo-Méndez MA Arnold AM Strub MP Hinshaw JE Taraska JW.
Nat Commun. 2025 Jan 2016(1):855.
doi: 10.1038/s41467-025-56045-z.
PMID: 39833141.
cryoET pipeline that enables imaging of large, ultra-thin areas of plasma membranes with angstrom-scale resolution.
=> genetically encodable, chemically-induced electron microscopy-visible tag to mark specific proteins, allowing for structural analysis in complex cellular environments. Suitable for targeted structural studies of plasma membrane proteins in mammalian cells.
Microbio
These are the 20 most-studied bacteria – the majority have been ignored.
Callaway E.
Nature. 2025 Jan 10.
doi: 10.1038/d41586-025-00038-x. Epub ahead of print.
PMID: 39794431.
Scientists have identified more than 45000 bacterial species — but just a handful of these have been deeply studied. Paul Jensen a microbial-systems biologist discovered that just 10 bacterial species account for half of all publications whereas nearly three-quarters of all named bacteria don’t have a single paper devoted to them. “Automating microbiology with robotics and artificial intelligence will accelerate our field but we need to apply these tools to the myriad species that live in the understudied corners of our world”
Miscellaneous
‘Never seen anything like this’: Trump’s team halts NIH meetings and travel.
Kozlov M.
Nature. 2025 Jan 23.
doi: 10.1038/d41586-025-00231-y. Epub ahead of print.
PMID: 39849141.
In an unprecedented move, research-grant reviews have been suspended indefinitely at the world’s largest public funder of biomedical research.
What Trump 2.0 means for science: the likely winners and losers.
Jones N, Witze A, Tollefson J, Kozlov M.
Nature. 2025 Jan;637(8046):532-535.
doi: 10.1038/d41586-025-00052-z.
PMID: 39815095.
The incoming US president is expected to gut support for research on the environment and infectious diseases, but could buoy work in artificial intelligence, quantum research and space exploration.
Keylabs et conséquences
https://themeta.news/keylabs-et-consequences/
Superstable lipid vacuoles endow cartilage with its shape and biomechanics.
Ramos R, et al.
Science. 2025 Jan 10;387(6730):eads9960.
doi: 10.1126/science.ads9960. Epub 2025 Jan 10.
PMID: 39787221.
External ears such as our own are made of a newly discovered form of lipid-filled cartilage that make them fabulously flexible. Researchers investigating vertebrates’ cartilaginous bits (which include the nose and larynx) looked at the ears of people and dozens of other mammal species and found that many share this ‘lipocartilage’ which wasn’t found in non-mammals. But our flappy flanges do have one big thing in common with the rest of the animal world found a separate study: to build ears mammals seem to reuse much of the cell types and gene programs that evolved to make gills in fish — and even farther back in the evolutionary story in invertebrates. “Our ears are potentially the evolutionary remnant of the first cartilage that existed” says developmental biologist and study co-author J. Gage Crump.
AI-designed proteins tackle century-old problem – making snake antivenoms.
Callaway E.
Nature. 2025 Jan;637(8047):776.
doi: 10.1038/d41586-025-00133-z.
PMID: 39814930.
Researchers have used AI to develop proteins that can block the deadly effects of snake venom. RFdiffusion to design ‘mini-binder’ proteins that attach to key regions of venom toxins to neutralize them. Mice injected with what would be a lethal dose of the venom all survived when given these mini-binders 15 minutes later.
Simulating 500 million years of evolution with a language model.
Hayes T, Rao R, Akin H, Sofroniew NJ, Oktay D, Lin Z, Verkuil R, Tran VQ, Deaton J, Wiggert M, Badkundri R, Shafkat I, Gong J, Derry A, Molina RS, Thomas N, Khan YA, Mishra C, Kim C, Bartie LJ, Nemeth M, Hsu PD, Sercu T, Candido S, Rives A.
Science. 2025 Jan 16:eads0018.
doi: 10.1126/science.ads0018. Epub ahead of print.
PMID: 39818825.
Language models trained at scale on evolutionary data can generate functional proteins that are far away from known proteins.
Here: use of ESM3 (multimodal generative language model that reasons over the sequence, structure, and function of proteins) to generate fluorescent proteins.
Authors found a bright fluorescent protein at a far distance (58% sequence identity) from known fluorescent proteins, estimated equivalent to simulating five hundred million years of evolution !!!