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@article{pmid41298376,

title = {Mechanistic basis of antimicrobial resistance mediated by the phosphoethanolamine transferase MCR-1},

author = {Allen P Zinkle and Mariana Bunoro Batista and Carmen M Herrera and Satchal K Erramilli and Brian Kloss and Khuram U Ashraf and Kamil Nosol and Guozhi Zhang and Rosemary J Cater and Michael T Marty and Anthony A Kossiakoff and M Stephen Trent and Rie Nygaard and Phillip J Stansfeld and Filippo Mancia},

doi = {10.1038/s41467-025-65515-3},

issn = {2041-1723},

year  = {2025},

date = {2025-11-01},

urldate = {2025-11-01},

journal = {Nat Commun},

volume = {16},

number = {1},

pages = {10516},

abstract = {Polymyxins are used to treat infections caused by multidrug-resistant Gram-negative bacteria. They are cationic peptides that target the negatively charged lipid A component of lipopolysaccharides, disrupting the outer membrane and lysing the cell. Polymyxin resistance is conferred by inner-membrane enzymes, such as phosphoethanolamine transferases, which add positively charged phosphoethanolamine to lipid A. Here, we present the structure of MCR-1, a plasmid-encoded phosphoethanolamine transferase, in its liganded form. The phosphatidylethanolamine donor substrate is bound near the active site in the periplasmic domain, and lipid A is bound over 20 Å away, within the transmembrane region. Integrating structural, biochemical, and drug-resistance data with computational analyses, we propose a two-state model in which the periplasmic domain rotates to bring the active site to lipid A, near the preferential phosphate modification site for MCR-1. This enzymatic mechanism may be generally applicable to other phosphoform transferases with large, globular soluble domains.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41254216,

title = {Temporal photoproximity labeling of ligand-activated EGFR neighborhoods using MultiMap},

author = {Zhi Lin and Wayne Ngo and Yu-Ting Chou and Harry Wu and Katherine J Susa and Young-Wook Jun and Trever G Bivona and Jennifer A Doudna and James A Wells},

doi = {10.1038/s41589-025-02076-y},

issn = {1552-4469},

year  = {2025},

date = {2025-11-01},

urldate = {2025-11-01},

journal = {Nat Chem Biol},

abstract = {Photoproximity labeling proteomics (PLP) methods have recently shown that cell surface receptors can form lateral interactome networks. Here, we present a paired set of PLP workflows that dynamically track neighborhood changes for oncogenic epidermal growth factor receptor (EGFR) over time, both outside and inside of cells. We achieved this by augmenting the multiscale PLP workflow we call MultiMap, where three photoprobes with different labeling ranges were photoactivated by one photocatalyst, eosin Y, anchored extracellularly and intracellularly on EGFR. We identified hundreds of neighboring proteins that changed within minutes to over 1 h after the addition of EGF. These neighborhoods reveal dynamic interactomes during early, middle and late signaling that drive phosphorylation, internalization, degradation and transcriptional regulation. This rapid 'molecular photographic' labeling approach provides snapshots of signaling neighborhoods, revealing their dynamic nature and potential for drug targeting.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41145429,

title = {Structural basis of drug recognition by human MATE1 transporter},

author = {Ksenija Romane and Giulia Peteani and Somnath Mukherjee and Julia Kowal and Lorenzo Rossi and Jingkai Hou and Anthony A Kossiakoff and Thomas Lemmin and Kaspar P Locher},

doi = {10.1038/s41467-025-64490-z},

issn = {2041-1723},

year  = {2025},

date = {2025-10-28},

urldate = {2025-10-01},

journal = {Nat Commun},

volume = {16},

number = {1},

pages = {9444},

abstract = {Human MATE1 (multidrug and toxin extrusion protein 1) is highly expressed in the kidney and liver, where it mediates the final step in the excretion of a broad range of cationic drugs, including the antidiabetic drug metformin, into the urine and bile. This transport process is essential for drug clearance and also affects therapeutic efficacy. To understand the molecular basis of drug recognition by hMATE1, we determined cryo-electron microscopy structures of the transporter in complex with the substrates 1-methyl-4-phenylpyridinium (MPP) and metformin and with the inhibitor cimetidine. The structures reveal a shared binding site located in a negatively charged pocket in the C-lobe of the protein. We functionally validated key interactions using radioactivity-based cellular uptake assays using hMATE1 mutants. Molecular dynamics simulations provide insights into the different binding modes and dynamic behaviour of the ligands within the pocket. Collectively, these findings define the structural basis of hMATE1 substrate specificity and shed light on its role in drug transport and drug-drug interactions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}