7DSX

Structure of a human NHE1-CHP1 complex under pH 7.5, bound by cariporide

Summary for 7DSX

• Entry DOI: 10.2210/pdb7dsx/pdb
• EMDB information: 30849
• Descriptor: Calcineurin B homologous protein 1, Sodium/hydrogen exchanger 1, (1S)-2-{[{[(2R)-2,3-DIHYDROXYPROPYL]OXY}(HYDROXY)PHOSPHORYL]OXY}-1-[(PALMITOYLOXY)METHYL]ETHYL STEARATE, ... (4 entities in total)
• Functional Keywords: transporter, membrane protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 162013.22

Authors

Dong, Y.,Gao, Y.,Li, B.,Zhang, X.C.,Zhao, Y. (deposition date: 2021-01-03, release date: 2021-06-23, Last modification date: 2024-03-27)

Primary citation

Dong, Y.,Gao, Y.,Ilie, A.,Kim, D.,Boucher, A.,Li, B.,Zhang, X.C.,Orlowski, J.,Zhao, Y.
Structure and mechanism of the human NHE1-CHP1 complex.
Nat Commun, 12:3474-3474, 2021

PubMed Abstract: Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.

PubMed: 34108458
DOI: 10.1038/s41467-021-23496-z

Experimental method

ELECTRON MICROSCOPY (3.5 Å)