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@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}

}

@article{pmid41091621,

title = {Hijacking Extracellular Targeted Protein Degrader-Drug Conjugates for Enhanced Drug Delivery},

author = {Fangzhu Zhao and Yan Wu and Kaitlin Schaefer and Yun Zhang and Kun Miao and Zi Yao and Snehal D Ganjave and Kaan Kumru and Trenton M Peters-Clarke and Alex Inague and James A Olzmann and Kevin K Leung and James A Wells},

doi = {10.1021/jacs.5c15047},

issn = {1520-5126},

year  = {2025},

date = {2025-10-15},

urldate = {2025-10-01},

journal = {J Am Chem Soc},

abstract = {Antibody-based therapeutics encompass diverse modalities for targeting tumor cells. Among these, antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. A major limitation of ADCs is their reliance on antigens with efficient internalization, while eTPD approaches, although capable of trafficking diverse targets to lysosomes, lack cytotoxic potency. To address this, we developed degrader-drug conjugates (DDCs), leveraging the endocytic and recycling activities of eTPD to enhance lysosomal delivery. We utilized fast internalizers, the low-density lipoprotein receptor (LDLR) and the chemokine receptor (CXCR7), to enhance lysosomal delivery. LDLR-based degraders enabled efficient and selective degradation of diverse extracellular membrane proteins, while DDCs with cytotoxic payload enhanced cytotoxicity compared to conventional ADCs . This dual modality addresses key challenges of inadequate internalization in conventional ADCs and cytotoxic potency in current eTPD strategies. Our findings demonstrate that DDCs provide additional optionality for developing next-generation antibody therapeutics with broader utility and improved efficacy in cancer treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40949987,

title = {A cytokine receptor-targeting chimera (kineTAC) toolbox for expanding extracellular targeted protein degradation},

author = {Kaan Kumru and Zi Yao and Brandon B Holmes and Fangzhu Zhao and Yun Zhang and Emilio Ferrara and Trenton M Peters-Clarke and Kevin K Leung and James A Wells},

doi = {10.1101/2025.09.02.673832},

issn = {2692-8205},

year  = {2025},

date = {2025-10-06},

urldate = {2025-09-01},

journal = {bioRxiv},

abstract = {Extracellular targeted protein degradation (eTPD) is as an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver. Cytokine receptor targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (Pance K, Gramespacher JA., Byrnes, JR, Salangsang F., Serrano JAC, Cotton AD, Steri V, and Wells JA,  , 41, 273-281). Here, we dramatically expand the kineTAC toolbox by constructing 81 new kineTACs based on an unbiased list of cytokines, chemokines and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues and some were more potent than the original CXCL12-based kineTAC. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type-selective eTPD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}