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| Open AccessStructure and mechanism of the K+/H+ exchanger KefC
Intracellular potassium (K+) homeostasis is achieved by activity of both ion channels and transporters. Here, the authors report structures of E. coli glutathione (GSH)-gated K+ efflux transporter KefC with bound K+ and conclude that the ion-binding site is adapted for binding a dehydrated ion.
- Ashutosh Gulati
- , Surabhi Kokane
- & David Drew
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Article
| Open AccessConformations of Bcs1L undergoing ATP hydrolysis suggest a concerted translocation mechanism for folded iron-sulfur protein substrate
How folded proteins are translocated across membranes is unknown for eukaryotes. Here, the authors propose a concerted translocation mechanism used by the AAA-ATPase Bcs1 to retro-translocate fully folded Rieske iron-sulfur protein across mitochondrial inner membrane.
- Jingyu Zhan
- , Allison Zeher
- & Di Xia
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Article
| Open AccessDynamics underlie the drug recognition mechanism by the efflux transporter EmrE
Here, the authors reveal the protonation of a single membrane embedded glutamate residue within the homodimer of the efflux transporter EmrE modulates the structure and dynamics in an allosteric manner using NMR spectroscopy.
- Jianping Li
- , Ampon Sae Her
- & Nathaniel J. Traaseth
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Article
| Open AccessProton-coupled transport mechanism of the efflux pump NorA
Efflux pumps confer antibiotic resistance by coupling proton import with drug export. In this work, the authors uncover the proton-coupled transport mechanism for the clinically relevant efflux pump NorA from the pathogenic bacterium S. aureus.
- Jianping Li
- , Yan Li
- & Nathaniel J. Traaseth
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Article
| Open AccessHairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Lipid droplet (LD) function relies on protein partitioning between the endoplasmic reticulum (ER) and LD. The authors show that UBXD8 adopts distinct conformations in both membranes and undergoes structural rearrangements during ER-to-LD partitioning.
- Ravi Dhiman
- , Rehani S. Perera
- & Bianca Schrul
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Article
| Open AccessStructure and inhibition of the human lysosomal transporter Sialin
Sialin transports multiple substrates including sialic acid out of lysosomes, and neurotransmitters into synaptic vesicles. This study reports the cryo-EM structures of Sialin in multiple states revealing its transport and pH-sensing mechanisms.
- Philip Schmiege
- , Linda Donnelly
- & Xiaochun Li
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Article
| Open AccessHeliorhodopsin-mediated light-modulation of ABC transporter
Here, authors classify genes flanking the Heliorhodopsin (HeR)-encoding genes and identify highly conserved residues for protein–protein interactions, revealing a function of HeR as regulatory rhodopsin for multidrug resistance.
- Shin-Gyu Cho
- , Ji-Hyun Kim
- & Kwang-Hwan Jung
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Article
| Open AccessStructural basis of human NOX5 activation
NADPH oxidase 5 (NOX5) is activated by Ca2+ signaling, catalyzing superoxide production by transferring electrons from intracellular NADPH to extracellular oxygen. Here the authors uncover the molecular basis of NOX5 activation and electron transfer.
- Chenxi Cui
- , Meiqin Jiang
- & Ji Sun
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Article
| Open AccessThe complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation
The amino acid transporter complex LAT1-4F2hc is considered a major drug target for many cancers. Here, the authors apply native mass spectrometry-based approaches to decode a complete LAT1-4F2hc assembly. To do this, they connect post-translational modification and endogenous phospholipid binding to super-dimerization, function and localisation of LAT1-4F2hc.
- Di Wu
- , Renhong Yan
- & Carol V. Robinson
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Article
| Open AccessAlternative splicing controls teneurin-3 compact dimer formation for neuronal recognition
This study reveals how two splice inserts alter the conformation and dimeric arrangement of the teneurin-3 extracellular region. These insights elucidate the role of teneurin isoforms in neuronal recognition and circuit wiring.
- Christos Gogou
- , J. Wouter Beugelink
- & Dimphna H. Meijer
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Article
| Open AccessSubstrate binding plasticity revealed by Cryo-EM structures of SLC26A2
SLC26A2 transports crucial ions and mutations in it cause diverse diseases. Here, authors present cryo-EM structures of SLC26A2 with substrates, revealing details of its homodimer assembly, dynamic substrate binding, and effects of mutations.
- Wenxin Hu
- , Alex Song
- & Hongjin Zheng
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Article
| Open AccessCross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies
The spatial mapping of proteins can give important functional insights. Here, Zhu et al. develop a cross-linking mass spectrometry-based spatial proteomics method that does not require protein engineering, affords sub-organelle resolution, and elucidates both protein locations and membrane topologies.
- Ying Zhu
- , Kerem Can Akkaya
- & Fan Liu
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Article
| Open AccessCryo-EM structure of the human Asc-1 transporter complex
The human Asc-1-4F2hc complex plays an important role in the neural development and stability. Here, authors determine the cryo-EM structures of Asc-1-4F2hc complex in three states, revealing its substrate recognition and transport mechanism.
- Yaning Li
- , Yingying Guo
- & Renhong Yan
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Article
| Open AccessStructure and mechanisms of transport of human Asc1/CD98hc amino acid transporter
Asc1/CD98hc is a key regulator of small neutral amino acid transport in the brain and adipose tissue. Here, authors report the structure of semi-occluded hAsc1/CD98hc and provide a model for Asc1 exchange and facilitated diffusion modes of transport.
- Josep Rullo-Tubau
- , Maria Martinez-Molledo
- & Oscar Llorca
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Article
| Open AccessCryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment
Gloeobacter proton-gated ion channel (GLIC) is a convenient model of pentameric ligand-gated ion channels. Here, Bharambe & Li et al. report structures and simulations of GLIC with insights into the role of lipids in GLIC gating mechanism.
- Nikhil Bharambe
- , Zhuowen Li
- & Sandip Basak
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Article
| Open AccessBidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA
ABC transporters are generally considered to be unidirectional. Here, the authors develop a fluorescence-based transport assay and show that the mycobacterial ABC transporter BacA instead acts as a bidirectional transporter for cobalamin.
- Mark Nijland
- , Solène N. Lefebvre
- & Dirk J. Slotboom
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Article
| Open AccessStructure of antiviral drug bulevirtide bound to hepatitis B and D virus receptor protein NTCP
Hepatitis B and D viruses require docking to the NTCP receptor protein for cell entry, an interaction that can be blocked by the drug bulevirtide. Here the authors use cryo-EM to reveal the structural basis of bulevirtide activity.
- Hongtao Liu
- , Dariusz Zakrzewicz
- & Kaspar P. Locher
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessStructure of full-length ERGIC-53 in complex with MCFD2 for cargo transport
ERGIC-53 engages in the ER-to-Golgi transport of secretory and membrane proteins by unknown mechanisms. Here authors report a long flexible tetrameric structure of full-length ERGIC-53 complexed with its functional partner MCFD2 by cryo-EM.
- Satoshi Watanabe
- , Yoshiaki Kise
- & Kenji Inaba
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Article
| Open AccessStructural basis for the modulation of MRP2 activity by phosphorylation and drugs
The ABC transporter MRP2/ABCC2 is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. Dysfunction leads to Dubin-Johnson syndrome. Here the authors provide structural and biochemical evidence on the modulation of MRP2 by intracellular kinases and inhibition by therapeutic drugs.
- Tiziano Mazza
- , Theodoros I. Roumeliotis
- & Konstantinos Beis
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Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
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Article
| Open AccessA co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation
Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Here, the authors develop LYTACAs, a modular supramolecular lysosome-targeting co-assembly system, as an effective platform for lysosomal degradation of extracellular and membrane proteins.
- Qian Wang
- , Xingyue Yang
- & Suwei Dong
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Article
| Open AccessEuglena’s atypical respiratory chain adapts to the discoidal cristae and flexible metabolism
Euglena gracilis is a model organism of the eukaryotic supergroup Discoba, single-celled organisms containing mitochondria with discoid cristae. Here, the authors report structures of Euglena’s transport chain supercomplex to reveal their distinctive architecture and working mechanisms.
- Zhaoxiang He
- , Mengchen Wu
- & Long Zhou
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Article
| Open AccessDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Understanding the molecular basis of voltage-sensing is of great importance in biology. Here, the authors use computational analysis and simulations to reveal atomic level insights into the mechanism of an isolated voltage-sensing domain.
- Spencer C. Guo
- , Rong Shen
- & Aaron R. Dinner
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Article
| Open AccessCryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin
The haematopoietic cytokine thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers. Here authors present a structural and biochemical characterization of how Tpo binds to its receptor to induce signaling.
- Kaiseal T. G. Sarson-Lawrence
- , Joshua M. Hardy
- & Nadia J. Kershaw
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Article
| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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Article
| Open AccessAssembly of a unique membrane complex in type VI secretion systems of Bacteroidota
The type VI secretion system (T6SS) of Gram-negative bacteria is typically anchored to the cell envelope through a membrane complex (MC), but Bacteroidota appear to lack genes encoding canonical MC components. Here, Bongiovanni et al. identify the Bacteroidota MC and study its biogenesis and connections with the conserved T6SS components.
- Thibault R. Bongiovanni
- , Casey J. Latario
- & Eric Durand
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Article
| Open AccessMechanism of anion exchange and small-molecule inhibition of pendrin
Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl−, I−, or HCO3−, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.
- Lie Wang
- , Anthony Hoang
- & Ming Zhou
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Article
| Open AccessTon motor conformational switch and peptidoglycan role in bacterial nutrient uptake
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
- Maximilian Zinke
- , Maylis Lejeune
- & Nadia Izadi-Pruneyre
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Article
| Open AccessThe juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation
Synaptotagmin (syt) 1 is a calcium sensor for neuronal exocytosis. Here, the authors show that the juxtamembrane linker of this integral membrane protein negatively regulates its calcium sensing activity by mediating self-association via liquid-liquid phase separation.
- Nikunj Mehta
- , Sayantan Mondal
- & Edwin R. Chapman
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Article
| Open AccessAllosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif
Drp1 is the master regulator of mitochondrial and peroxisomal fission. Here, the authors show that a C-terminal intrinsically disordered motif, named the CT-SLiM, constitutes an allosteric switch that controls Drp1 structure, assembly, and function.
- Isabel Pérez-Jover
- , Kristy Rochon
- & Rajesh Ramachandran
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Article
| Open AccessHijacking of internal calcium dynamics by intracellularly residing viral rhodopsins
Rhodopsins are ubiquitous light-driven membrane proteins that have diverse functions in nature, and value as optogenetics tools. Here the authors characterise type 1 viral channelrhodopsins, showing that they regulate intracellular calcium and can be used for the photocontrol of muscle contraction in vivo.
- Ana-Sofia Eria-Oliveira
- , Mathilde Folacci
- & Michel Vivaudou
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Article
| Open AccessMolecular mechanism of phospholipid transport at the bacterial outer membrane interface
Maintenance of lipid asymmetry in the bacterial outer membrane (OM) is mediated by the OmpC-Mla system, but mechanistic details remain to be elucidated. Here, the authors show that electrostatic interactions, conformational dynamics, and membrane thinning may facilitate spontaneous retrograde phospholipid transfer at the OM.
- Jiang Yeow
- , Min Luo
- & Shu-Sin Chng
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessTransmembrane coupling of liquid-like protein condensates
Using a freestanding planar lipid membrane system, the authors show that liquid-like protein condensates on one side of a lipid membrane colocalize with those on the opposite side, suggesting a mechanism of information transfer across biological membranes.
- Yohan Lee
- , Sujin Park
- & Jeanne C. Stachowiak
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Article
| Open AccessActivation and substrate specificity of the human P4-ATPase ATP8B1
Asymmetric phospholipid distribution in cell membranes is vital for cellular function. Here, authors reveal how ATP8B1, a P4-ATPase, can transport different lipids, including phosphatidylinositol.
- Thibaud Dieudonné
- , Felix Kümmerer
- & Poul Nissen
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Article
| Open AccessThe GET insertase exhibits conformational plasticity and induces membrane thinning
Tail-anchored (TA) membrane protein biogenesis is mediated by the GET insertase. Here, authors present cryo-EM and X-ray structures, MD simulations and functional data for human and fungal insertases showing membrane remodeling for TA insertion.
- Melanie A. McDowell
- , Michael Heimes
- & Irmgard Sinning
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Article
| Open AccessStructural basis of bile salt extrusion and small-molecule inhibition in human BSEP
BSEP (ABCB11) is expressed in hepatocytes and extrudes bile salts into the canaliculi of the liver. Here, authors report cryo-EM structures of BSEP providing structural and functional insight into the mechanism of bile salt extrusion and small-molecule inhibition.
- Hongtao Liu
- , Rossitza N. Irobalieva
- & Kaspar P. Locher
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Article
| Open AccessStructural basis for ligand recognition and signaling of hydroxy-carboxylic acid receptor 2
Niacin is used to treat cardiovascular disease through its activation of the GPCR HCAR2. Here, the authors present cryo-EM structures of HCAR2 bound to niacin and other drug-like small molecules, which explain the basis of HCAR2 ligand recognition.
- Jae-Hyun Park
- , Kouki Kawakami
- & Sam-Yong Park
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Article
| Open AccessStructure of a membrane-bound menaquinol:organohalide oxidoreductase
The structure of a bacterial membrane protein complex involved in the bioremediation of tetrachloroethene, a major chlorinated organic pollutant, was determined. It elucidates the path of electrons from menaquinol to the active site of the enzyme.
- Lorenzo Cimmino
- , Américo G. Duarte
- & Julien Maillard
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Article
| Open AccessStructural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
- Navid Paknejad
- , Vinay Sapuru
- & Richard K. Hite
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessFibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis
Fibrocystin/Polyductin (FPC) is a large ciliary membrane protein encoded by PKHD1 which, when mutated, causes ARPKD. Here, the authors show that FPC suppresses cyst development in the kidney of mouse models through the release and mitochondrial translocation of its C terminal product.
- Rebecca V Walker
- , Qin Yao
- & Feng Qian
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Article
| Open AccessStructural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410
Triacylglycerides help to secure the impermeability of mycobacterial cell envelope to some drugs. Here, authors solve the structure of the triacylglyceride transporter Rv1410 and proposed a molecular mechanism for triacylglyceride extraction.
- Sille Remm
- , Dario De Vecchis
- & Markus A. Seeger
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Article
| Open AccessStructural conservation of insulin/IGF signalling axis at the insulin receptors level in Drosophila and humans
Insulin hormones and their receptors regulate key life processes in animals: from metabolism to life span. Human insulin receptor has been studied extensively. Here, the authors show remarkable structural similarity of fruit fly and human insulin receptors, indicating their universal functioning.
- Cristina M. Viola
- , Orsolya Frittmann
- & Andrzej M. Brzozowski
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Article
| Open AccessA conserved membrane protein negatively regulates Mce1 complexes in mycobacteria
Mycobacterial Mce systems are putative ABC transporters for lipids. Here, the authors revealed two distinct Mce1 complexes comprising different heterohexameric substrate binding assemblies that are negatively regulated via a novel mechanism.
- Yushu Chen
- , Yuchun Wang
- & Shu-Sin Chng
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Article
| Open AccessStructure of human drug transporters OATP1B1 and OATP1B3
A key step of drug metabolism in the human body is the uptake into liver cells, which is mediated by transport proteins of the OATP family. Here, authors report cryo-EM structures of two human OATP proteins, providing insight into their function.
- Anca-Denise Ciută
- , Kamil Nosol
- & Kaspar P. Locher
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Article
| Open AccessHigh-throughput screening of BAM inhibitors in native membrane environment
The bacterial insertase BAM is a key target for novel antibiotics that are urgently needed. Here, we describe the implementation of an assay that allows screening for BAM inhibitors in the native membrane in high-throughput format.
- Parthasarathi Rath
- , Adrian Hermann
- & Sebastian Hiller
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Article
| Open AccessThe net electrostatic potential and hydration of ABCG2 affect substrate transport
ABCG2, an ATP-binding cassette transporter, extrudes hundreds of hydrophilic and hydrophobic compounds from cells, playing roles in xenobiotic clearance or multidrug resistance in cancer. Gose et al provide key insights into ABCG2 substrate selection.
- Tomoka Gose
- , Heather M. Aitken
- & John D. Schuetz