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Structural and Functional Insights into Membrane Transporters: A Tribute to Dr. Ernest Wright

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 3887

Special Issue Editor

Prof. Dr. Jeff Abramson

E-Mail Website
Guest Editor
Department of Physiology, School of Medicine, University of California, Los Angeles, CA 90095, USA
Interests: transporters; channnbels; biophysics; crystallography; cryo-EM

Special Issue Information

Dear Colleagues,

This Special Issue will commemorate the outstanding career of Dr. Ernest Wright, who has recently retired. Dr. Wright, a member of both the Royal Society and the National Academy of Sciences, is renowned for his pioneering contributions to the field of membrane transport, particularly in the cloning and characterization of sodium-glucose co-transporters (SGLTs). His groundbreaking discoveries have shaped our understanding of glucose transport and its implications for human health, laying the foundation for therapeutic advances in diabetes and cancer treatment.

This Special Issue will take a broader approach to membrane transporters, examining various classes of transporters and exploring their structural and functional relationships, as well as their roles in health and disease. By bringing together cutting-edge research, this Special Issue will provide a comprehensive overview of how membrane transporters contribute to cellular function and how their dysfunction can lead to disease.

It is our honor to celebrate Dr. Wright’s illustrious career with this collection of studies, which will also inspire future research in the field of membrane transport.

Prof. Dr. Jeff Abramson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • membrane transporters
  • membrane protein
  • glucose transport
  • cell membrane
  • interface reaction

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Published Papers (3 papers)

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Research

19 pages, 6883 KB  
Article
Interactions of Arachidonic Acid with AAC1 and UCP1
by Jonathan H. Borowsky and Michael Grabe
Int. J. Mol. Sci. 2025, 26(21), 10504; https://doi.org/10.3390/ijms262110504 - 29 Oct 2025
Viewed by 405
Abstract
The inner mitochondrial membrane proteins ATP/ADP carrier protein 1 (AAC1) and Uncoupling protein 1 (UCP1) belong to the SLC25 mitochondrial carrier family. AAC1 is responsible for ATP/ADP exchange, while UCP1-dependent proton transport, which also requires small molecules known as activators, is the basis [...] Read more.
The inner mitochondrial membrane proteins ATP/ADP carrier protein 1 (AAC1) and Uncoupling protein 1 (UCP1) belong to the SLC25 mitochondrial carrier family. AAC1 is responsible for ATP/ADP exchange, while UCP1-dependent proton transport, which also requires small molecules known as activators, is the basis of brown fat thermogenesis. Arachidonic acid (AA) is an endogenous activator capable of inducing proton transport in both proteins. As such, both AAC1- and UCP1-dependent proton transport are potential targets of weight loss drugs. While AAC1 structures have long been available, only recently have structures of UCP1 been determined. Unfortunately, no AA-bound structure of either protein is available. To explore their interactions with AA, we performed molecular dynamics (MD) simulations of both proteins. Six parallel simulations of each protein were run with an average length of just over 6 μs, for a total of 75 μs of aggregate simulation across both proteins. AA bound deeply between transmembrane helix (TM) helices or in the central cavity of AAC1 in 14 events and between TM helices of UCP1 in 6 events. All AA involved in these deep binding events came from the intermembrane space-facing (C) leaflet. In AAC1, AA most often bound between TM1/TM2 and TM5/TM6. In four cases the fatty acid bound at the bottom of the central cavity rather than in an interhelical groove. In UCP1, all but one deeply bound AA sat between TM5 and TM6. No AA fully entered the cavity as observed in AAC1. In addition to entering the proteins, AAs were enriched around them in the surrounding membrane adjacent to the TM helices. While both protein structures exhibit hydrophobic stretches separating the intermembrane space (IMS) from the matrix, water wires formed through both AAC1 and UCP1, connecting the bulk water in both regions. Grotthuss shuttling along water wires has been proposed as a possible mechanism of AAC1/UCP1-dependent proton transport, but water wires are not present in experimental structures and have not previously been reported in MD simulations. Calculations of electric potentials along these water wires find a large 0.75–1 V electrostatic barrier along water wires through AAC1 and a substantially smaller such barrier of ~0.5 V through UCP1. Full article
(This article belongs to the Special Issue Structural and Functional Insights into Membrane Transporters: A Tribute to Dr. Ernest Wright)
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19 pages, 5451 KB  
Article
Isorhamnetin Modulates Drug-Resistance-Related Biomarkers in Colon Cancer Cells
by Nikola Radenković, Dejan Milenković, Danijela Nikodijević, Sofija Jovanović Stojanov, Ana Podolski Renić and Milena Milutinović
Int. J. Mol. Sci. 2025, 26(13), 6208; https://doi.org/10.3390/ijms26136208 - 27 Jun 2025
Viewed by 1010
Abstract
The development of resistance to standard cytostatics, such as 5-fluorouracil (5-FU), significantly limits the efficacy of colon cancer therapy, prompting the search for novel anticancer agents, particularly among natural compounds. This study evaluated the anticancer effects of isorhamnetin, a plant-derived flavonol, and its [...] Read more.
The development of resistance to standard cytostatics, such as 5-fluorouracil (5-FU), significantly limits the efficacy of colon cancer therapy, prompting the search for novel anticancer agents, particularly among natural compounds. This study evaluated the anticancer effects of isorhamnetin, a plant-derived flavonol, and its ability to modulate the expression of drug-resistance-related biomarkers in SW-480 and HT-29 colon cancer cells, with a focus on ATP-binding cassette (ABC) transporters. Isorhamnetin demonstrated strong cytotoxic and proapoptotic activity on both cell lines, while showing lower toxicity toward normal HaCaT cells. In addition to suppressing the mRNA expression of drug-metabolizing enzymes (CYP1A1 and CYP1B1), isorhamnetin significantly reduced the mRNA levels of multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5), as well as the P-glycoprotein (P-gp) level in SW-480 and HT-29 cells. Molecular docking analysis revealed a high binding affinity of isorhamnetin to CYP1A1, CYP1B1, P-gp, MRP1, MRP5, and glutathione S-transferase (GST) proteins, with stronger interactions than those observed for 5-FU, suggesting potential interference with their function. These results provide a solid basis for future investigations to confirm the therapeutic potential of isorhamnetin as a modulator of drug resistance in colon cancer cells. Full article
(This article belongs to the Special Issue Structural and Functional Insights into Membrane Transporters: A Tribute to Dr. Ernest Wright)
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20 pages, 9252 KB  
Article
Structure and Inhibition of the Human Na+/H+ Exchanger SLC9B2
by Sukkyeong Jung, Surabhi Kokane, Hang Li, So Iwata, Norimichi Nomura and David Drew
Int. J. Mol. Sci. 2025, 26(9), 4221; https://doi.org/10.3390/ijms26094221 - 29 Apr 2025
Viewed by 1794
Abstract
The sodium/proton exchanger NHA2, also known as SLC9B2, is important for insulin secretion, renal blood pressure regulation, and electrolyte retention. Recent structures of bison NHA2 has revealed its unique 14-transmembrane helix architecture, which is different from SLC9A/NHE members made up from 13-TM helices. [...] Read more.
The sodium/proton exchanger NHA2, also known as SLC9B2, is important for insulin secretion, renal blood pressure regulation, and electrolyte retention. Recent structures of bison NHA2 has revealed its unique 14-transmembrane helix architecture, which is different from SLC9A/NHE members made up from 13-TM helices. Sodium/proton exchangers are functional homodimers, and the additional N-terminal helix in NHA2 was found to alter homodimer assembly. Here, we present the cryo-electron microscopy structures of apo human NHA2 in complex with a Fab fragment and also with the inhibitor phloretin bound at 2.8 and 2.9 Å resolution, respectively. We show how phosphatidic acid (PA) lipids bind to the homodimer interface of NHA2 on the extracellular side, which we propose has a regulatory role linked to cell volume regulation. The ion binding site of human NHA2 has a salt bridge interaction between the ion binding aspartate D278 and R432, an interaction previously broken in the bison NHA2 structure, and these differences suggest a possible ion coupling mechanism. Lastly, the human NHA2 structure in complex with phloretin offers a template for structure-guided drug design, potentially leading to the development of more selective and potent NHA2 inhibitors. Full article
(This article belongs to the Special Issue Structural and Functional Insights into Membrane Transporters: A Tribute to Dr. Ernest Wright)
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