{"entity": "publication", "iuid": "7fe5c5e91f3b4115811b892799b43070", "timestamp": "2026-09-25T18:01:21.988Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/7fe5c5e91f3b4115811b892799b43070.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/7fe5c5e91f3b4115811b892799b43070"}}, "title": "Structure and Inhibition of the Human Na+/H+ Exchanger SLC9B2.", "authors": [{"family": "Jung", "given": "Sukkyeong", "initials": "S"}, {"family": "Kokane", "given": "Surabhi", "initials": "S"}, {"family": "Li", "given": "Hang", "initials": "H"}, {"family": "Iwata", "given": "So", "initials": "S"}, {"family": "Nomura", "given": "Norimichi", "initials": "N", "orcid": "0000-0002-6330-2239", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/24130b4b08334bc693032fab14dc5eb1.json"}}, {"family": "Drew", "given": "David", "initials": "D", "orcid": "0000-0001-8866-6349", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/e80593c5f1ec4f87a38b079e5909f0b0.json"}}], "type": "journal article", "published": "2025-04-29", "journal": {"title": "Int J Mol Sci", "issn": "1422-0067", "volume": "26", "issue": "9", "issn-l": null}, "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. 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 \u00c5 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.", "doi": "10.3390/ijms26094221", "pmid": "40362458", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12072577"}, {"db": "pii", "key": "ijms26094221"}], "notes": [], "created": "2026-09-23T12:32:36.226Z", "modified": "2026-09-23T12:32:36.268Z"}