Substrate binding and inhibition of the anion exchanger 1 transporter

Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO 2 transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regula...

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Published inNature structural & molecular biology Vol. 30; no. 10; pp. 1495 - 1504
Main Authors Capper, Michael J., Yang, Shifan, Stone, Alexander C., Vatansever, Sezen, Zilberg, Gregory, Mathiharan, Yamuna Kalyani, Habib, Raul, Hutchinson, Keino, Zhao, Yihan, Schlessinger, Avner, Mezei, Mihaly, Osman, Roman, Zhang, Bin, Wacker, Daniel
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.10.2023
Nature Publishing Group
Subjects
631/45/612/1237
631/535/1258/1259
Anion Exchange Protein 1, Erythrocyte - chemistry
Anion Exchange Protein 1, Erythrocyte - metabolism
Anion exchanging
Antigens
Bicarbonates
Bicarbonates - metabolism
Binding Sites
Biochemistry
Biological Microscopy
Biomedical and Life Sciences
Blood groups
Carbon dioxide
Carrier transport
Data collection
Drugs
Erythrocytes
Feature recognition
Inhibitors
Life Sciences
Ligands
Lipids
Medicine
Membrane Biology
Membrane Transport Proteins - metabolism
Molecular biology
Protein Domains
Protein Structure
Sterols
Substrate inhibition
Substrates
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Summary:Anion exchanger 1 (AE1), a member of the solute carrier (SLC) family, is the primary bicarbonate transporter in erythrocytes, regulating pH levels and CO 2 transport between lungs and tissues. Previous studies characterized its role in erythrocyte structure and provided insight into transport regulation. However, key questions remain regarding substrate binding and transport, mechanisms of drug inhibition and modulation by membrane components. Here we present seven cryo-EM structures in apo, bicarbonate-bound and inhibitor-bound states. These, combined with uptake and computational studies, reveal important molecular features of substrate recognition and transport, and illuminate sterol binding sites, to elucidate distinct inhibitory mechanisms of research chemicals and prescription drugs. We further probe the substrate binding site via structure-based ligand screening, identifying an AE1 inhibitor. Together, our findings provide insight into mechanisms of solute carrier transport and inhibition. Capper et al. uncover how bicarbonate binds to the anion exchanger 1 (AE1), elucidate how drugs inhibit AE1 via distinct mechanisms, and generate a series of AE1 inhibitors using structure-based drug discovery.
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M.J.C. designed experiments, expressed and purified protein for grid freezing, collected data, refined structures and edited the manuscript. S.Y. and A.C.S. purified protein, prepared samples for grid freezing, established and performed functional assays and edited the manuscript. S.V. performed molecular docking calculations with help from Y.Z., and helped analyze the structures. G.Z. prepared grids for structure determination and assisted with data collection, processing and refinement. Y.K.M. helped with data processing and structure refinement. R.H. helped establish protein expression and purification. K.H. performed volume calculations. A.S. supervised docking and volume calculation experiments and helped write the paper. R.O. performed molecular simulations and SACP analysis of substrate binding with help from M.M. B.Z. contributed to the study design and supervised computational studies. D.W. designed experiments, analyzed the data, supervised the overall project and management and wrote the manuscript.
Author contributions
ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/s41594-023-01085-6