MP
Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.
Li P, Zhu Z, Wang Y, Zhang X, Yang C, Zhu Y, Zhou Z, Chao Y, Long Y, Gao Y, Liu S, Zhang L, Gao P, Qu Q.
Nat Commun. 2024 Dec 30;15(1):10924.
doi: 10.1038/s41467-024-55359-8.
PMID: 39738067.
Cellular uptake of thiamine and pyridoxine (= essential B vitamins) is regulated by the transporters SLC19A2 and SLC19A3.
Genetic mutations or drugs like metformin and fedratinib => deficiencies and severe neurometabolic diseases.
Here: cryo-EM structures reveal mechanisms of substrate and drug recognition => insights into drug-nutrient interactions and their physiological significance.
Higher-order transient membrane protein structures.
Zhang Y, Mazal H, Mandala VS, Pérez-Mitta G, Sondoghdar V, Haselwandter CA, MacKinnon R.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2421275121.
doi: 10.1073/pnas.2421275121. Epub 2024 Dec 31.
PMID: 39739811.
Study demonstrating that 5 MPs self-cluster into higher-order transient structures (HOTS) through weak, reversible interactions under natural expression levels.
Elevated concentrations => clusters exhibit a critical distribution => phase transition (larger bulk phase clusters, akin to micellization).
Higher-order transient structures and the principle of dynamic connectivity in membrane signaling.
Zhang Y, MacKinnon R.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2421280121.
doi: 10.1073/pnas.2421280121. Epub 2024 Dec 31.
PMID: 39739805.
Higher-order transient structures (HOTS) mediate M2R regulation of GIRK channels => statistical bias for these proteins to cluster near each other.
Weak, transient interactions shape the spatial distribution and electrophysiological activity. The concept of dynamic connectivity is proposed, where weak multivalent interactions within and between HOTS facilitate communication in membrane signaling pathways.
Structures of methane and ammonia monooxygenases in native membranes.
Tucci FJ, Rosenzweig AC.
Proc Natl Acad Sci U S A. 2025 Jan 7;122(1):e2417993121.
doi: 10.1073/pnas.2417993121. Epub 2024 Dec 31.
PMID: 39739801.
Methane- and ammonia-oxidizing bacteria use copper membrane monooxygenases (pMMO and AMO) to oxidize methane to methanol and ammonia to hydroxylamine, respectively.
Here: cryoEM of these enzymes directly in their native membrane environments => detailed structures of copper centers, bound lipids, and novel supernumerary helices that may regulate activity or array formation.
Interaction of unphosphorylated PtsN with the K+/H+ antiporter YcgO inhibits its activity in Escherichia coli.
Patidar Y, Athreya A, Sharma R, Penmatsa A, Sardesai AA.
J Biol Chem. 2024 Dec 30:108153.
doi: 10.1016/j.jbc.2024.108153. Epub ahead of print.
PMID: 39742999.
Unphosphorylated PtsN negatively regulates K⁺ efflux through YcgO, a CPA1 family cation/proton antiporter.
Unphospho-PtsN specifically interacts with the C-terminal cytoplasmic region of YcgO while phosphorylation of PtsN weakens this interaction.
Targeted degradation of membrane proteins.
Hohman G, Shahid M, Eldeeb M.
Nat Struct Mol Biol. 2024 Dec 31.
doi: 10.1038/s41594-024-01461-w. Epub ahead of print.
PMID: 39741225.
Targeted protein degradation = promising drug discovery approach.
Here: transferrin receptor targeting chimeras (TransTACS), which lysosomally degrade MPs with potent specificity and efficacy. TransTACs reversibly regulate the tumor-killing activity of CAR-T cells and inhibit drug-resistant EGFR-driven cancers in mice.
ref article: Zhang D et al. Nature. 2024 PMID: 39322661 (cf. 20240930_membrane digest ;-D).
Orthogonal validation of PROTAC mediated degradation of the integral membrane proteins EGFR and c-MET.
Ruffilli C, Röth S, Zelcer N, Moreau K.
Sci Rep. 2025 Jan 2;15(1):504.
doi: 10.1038/s41598-024-84217-2.
PMID: 39748066
MPs = crucial drug targets due to their involvement in numerous diseases, but PROTAC technology’s application to MPs remains limited.
Here: comparison of immunoblotting, flow cytometry, and immunofluorescence to evaluate PROTAC-mediated degradation of EGFR and c-MET, highlighting each method’s strengths and limitations.
Immunofluorescence and flow cytometry = recommended for their ability to provide both qualitative and quantitative insights into degradation efficacy while distinguishing between membrane-localized and intracellular MP pools.
Molecular basis for the activation of Pseudomonas aeruginosa MsbA by Zn2+.
Jixing Lyu, Hanieh Bahramimoghaddam, Tianqi Zhang, Gaya Yadav, Minglei Zhao, David Russell, and Arthur Laganowsky.
bioRxiv posted 2 January 2025.
doi:10.1101/2024.12.31.630943.
Constant pH Molecular Dynamics (CpHMD) simulations = powerful method to study biological systems with high realism.
Here: demonstration of the use of CpHMD to explore the pH-dependent behavior of Cationic Ionizable Lipids, key to optimizing Lipid Nanoparticles for drug delivery, including mRNA vaccines.
=> detailed protocol for simulating CIL-containing membranes and calculating apparent pKa values.
Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.
Conflitti P, Lyman E, Sansom MSP, Hildebrand PW, Gutiérrez-de-Terán H, Carloni P, Ansell TB, Yuan S, Barth P, Robinson AS, Tate CG, Gloriam D, Grzesiek S, Eddy MT, Prosser S, Limongelli V.
Nat Rev Drug Discov. 2025 Jan 2.
doi: 10.1038/s41573-024-01083-3. Online ahead of print.
PMID: 39747671.
Review highlighting progress in targeting GPCRs with allosteric modulators, biased ligands, and bivalent or bitopic compounds.
Membrane
Biomolecular Condensates can Induce Local Membrane Potentials.
Anthony Gurunian, Keren Lasker, Ashok A. Deniz.
bioRxiv 2024.12.27.630407;
doi: https://doi.org/10.1101/2024.12.27.630407.
Biomolecular condensates (selective compartmentalization of biomolecules without lipid membranes), interact with lipid membranes in processes like autophagy and T-cell activation.
Here: charged poly-lysine/ATP condensates can induce localized membrane potentials in GUVs, an effect modulated by salt concentration and ATP-to-poly-lysine ratios.
Supported by electro-thermodynamic modeling, these findings suggest that condensate charge plays a key role, with implications for processes like neuronal signaling where condensates may regulate membrane potential.
Alternative lipid synthesis in response to phosphate limitation promotes antibiotic tolerance in Gram-negative ESKAPE pathogens.
Roberto Jhonatan Olea-Ozuna, Melanie J Campbell, Samantha Y Quintanilla, Sinjini Nandy, Jennifer S Brodbelt, and Joseph M Boll.
bioRxiv posted 31 December 2024.
doi:10.1101/2024.09.11.612458.
Study identifying an alternative lipid biosynthesis pathway in ESKAPE pathogens, where phosphate starvation induces the replacement of glycerophospholipids with zwitterionic ornithine and lysine, enabling survival against colistin.
=> targeting aminolipid biosynthesis could provide a strategy to improve treatment efficacy against antibiotic-resistant Gram-negative infections.
Role of the transmembrane polar residues on CD151 in cholesterol binding.
Sahu VK, Lokhande KB, Swamy VK, Basu S, Ranjan A.
J Biomol Struct Dyn. 2025 Jan 1:1-13.
doi: 10.1080/07391102.2024.2446663. Epub ahead of print.
PMID: 39743780.
Tetraspanins, including CD151, play key roles in cancer metastasis, with polar residues in their TM domains influencing their function.
Here: identification of three conserved polar residues in CD151 that are critical for cholesterol binding, protein stability, and the open/closed conformation of the protein.
Force Generation by Enhanced Diffusion in Enzyme-Loaded Vesicles.
Eike Eberhard, Ludwig Burger, Cesar L. Pastrana, Hamid Seyed-Allaei, Giovanni Giunta, and Ulrich Gerland.
bioRxiv posted 2 January 2025.
doi:10.1101/2025.01.02.627955.
Recent experiments showed that enhanced diffusion (where diffusion coefficient of metabolic enzymes increases with substrate concentration) can cause non-homogeneous enzyme distribution.
In enzyme-loaded vesicles exposed to substrate gradients, enhanced diffusion => pressure gradient, leading to vesicle deformation and self-propulsion.
Here: simulations and modeling to characterize these effects => insights into enhanced diffusion’s potential for designing novel synthetic cargo transporters, such as targeted drug delivery systems.
The mycomembrane differentially and heterogeneously restricts antibiotic permeation.
Irene Lepori, Kiserain Jackson, Zichen Liu, Mahendra D Chordia, Mitchell Wong, Sylvia L Rivera, Marta Roncetti, Laura Poliseno, Marcos M Pires, and M. Sloan Siegrist.
bioRxiv posted 2 January 2025.
doi:10.1101/2024.12.31.630956.
Impermeability of Mycobacterium tuberculosis to antibiotics = largely attributed to its outer mycomembrane, but previous studies were indirect or relied on bulk measurements.
Here: study shows that the mycomembrane selectively restricts access to fluorophores and antibiotic derivatives, with differential effects across antibiotic classes and families, such as fluoroquinolones.
+ heterogeneity in how different molecules, like fluorophores and vancomycin, are restricted by the mycomembrane.
ABC transporter activity is affected by the size of lipid nanodiscs.
Nouel Barreto A, Cuello LG, Zoghbi ME.
FEBS Lett. 2025 Jan 2.
doi: 10.1002/1873-3468.15096. Online ahead of print.
PMID: 39748569
Systematic study to determine the effect of the ND size on the ATPase activity of model ABC transporters from human, plant, and bacteria.
=> the activity of the transporters and their response to regulatory molecules is affected by the nanodisc size: use of larger MSPs (ex: MSP2N2) minimize alterations caused by the commonly used small MSP1D1.
Methods
A fiducial-assisted strategy compatible with resolving small MFS transporter structures in multiple conformations using cryo-EM.
Xie P Li Y Lamon G Kuang H Wang DN Traaseth NJ.
Nat Commun. 2025 Jan 216(1):7.
doi: 10.1038/s41467-024-54986-5.
PMID: 39746942
Studying MPs near the 40 kDa size threshold by cryoEM = challenging due to image alignment issues and difficulty resolving multiple conformations.
Here: strategy using a rigid BRIL domain marker at the C-terminus of MFS transporters, combined with AF2 predictions, to enable cryoEM analysis of conformational landscapes.
=> 4 structures of NorA + validation on 3 other MFS transporters.
Peptidisc-assisted hydrophobic clustering towards the production of multimeric and multispecific nanobody proteins.
Franck Duong and Yilun Chen.
bioRxiv posted 1 January 2025.
doi:10.1101/2024.12.31.630897.
Protein multimerization (e.g tandem linking, self-assembly fusion, and cross-linking) => enhancement of stability, diversity, and function.
Here: novel approach using the peptidisc membrane mimetic to stabilize hydrophobic-driven protein associations, applied to Nbs, which form multimeric assemblies called “polybodies” (Pbs).
=> increased affinity through avidity effects => creation of bispecific and auto-fluorescent Pbs => expands protein engineering strategies for generating multispecific and multifunctional protein entities.
Microbio
Intracellular Quantification of an Antibiotic Metal Complex in Single Cells of Escherichia coli Using Cryo-X-ray Fluorescence Nanoimaging.
Draveny M, Chauvet H, Rouam V, Jamme F, Masi M.
ACS Nano. 2024 Dec 31.
doi: 10.1021/acsnano.4c12664. Epub ahead of print.
PMID: 39740123.
Spectrofluorimetry and synchrotron radiation-based DUV microscopy have previously been used for monitoring the accumulation of fluoroquinolones in bacteria at population and single-cell scales.
Here: cryo-XRF nanoimaging for the intracellular localization and quantification of a fluoroquinolone metal complex accumulation in E.coli with different efflux pump expression levels.
Emergence of the mobile RND-type efflux pump gene cluster tmexCD1-toprJ1 in Klebsiella pneumoniae clinical isolates in Japan.
Hirabayashi A Yano H Yahara K Aoki S Sugawara Y Kajihara T Shibayama N Kayama S Suzuki M Sugai M.
J Antimicrob Chemother. 2025 Jan 380(1):192-199.
doi: 10.1093/jac/dkae395.
PMID: 39504488
Investigation of the prevalence of the tigecycline resistance gene cluster tnfxB-tmexCD-toprJ in clinical isolates of Enterobacterales in Japan. The gene cluster was found in two Klebsiella pneumoniae isolates, both carrying plasmids with multiple antimicrobial resistance genes, including extended-spectrum β-lactamases. Despite the rare clinical use of tigecycline in Japan, the presence of this resistance cluster highlights a significant public health threat that requires ongoing monitoring.
Miscellaneous
How AI is unlocking ancient texts – and could rewrite history.
Marchant J.
Nature. 2025 Jan;637(8044):14-17.
doi: 10.1038/d41586-024-04161-z.
PMID: 39739096.
Last February, student researchers used machine learning to decipher the text hidden inside a charred, unopenable scroll from the ancient Roman city of Herculaneum. Now artificial neural networks are being used to translate the vast historical archives of Korean kings and decipher ancient languages of which only scraps of text survive.
Do insect have feelings ?
Shayla Love
January 5, 2025
The New Yorker
The roll-call of creatures recognized by law as sentient — capable of feelings such as joy and fear — has expanded beyond the easily anthropomorphizable to animals such as octopuses and lobsters. So why not insects? Scientists have started to explore whether insects go beyond simple ‘reflex machines’ with experiments that aim to reveal something about their inner lives.
Slow productivity worked for Marie Curie – here’s why you should adopt it, too.
Gulland A.
Nature. 2024 Aug;632(8024):461-463.
doi: 10.1038/d41586-024-02540-0.
PMID: 39103528.
Do fewer things, work at a natural pace and obsess over quality, says computer scientist Cal Newport, in his latest time-management book.
The animated guide to a Ph.D.
https://www.youtube.com/watch?v=We760YM5-iM