6C1P

HypoPP mutant

Summary for 6C1P

• Entry DOI: 10.2210/pdb6c1p/pdb
• Descriptor: Ion transport protein, PHOSPHATE ION, 1,2-DIMYRISTOYL-SN-GLYCERO-3-PHOSPHOCHOLINE, ... (4 entities in total)
• Functional Keywords: mutant, metal transport
• Biological source: Arcobacter butzleri (strain RM4018)
• Total number of polymer chains: 4
• Total formula weight: 143025.72

Authors

Catterall, W.A.,Zheng, N.,Jiang, D.,Gamal El-Din, T.M. (deposition date: 2018-01-05, release date: 2018-05-16, Last modification date: 2023-10-04)

Primary citation

Jiang, D.,Gamal El-Din, T.M.,Ing, C.,Lu, P.,Pomes, R.,Zheng, N.,Catterall, W.A.
Structural basis for gating pore current in periodic paralysis.
Nature, 557:590-594, 2018

PubMed Abstract: Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Na1.4 or the calcium channel Ca1.1. Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis owing to cation leak in both activated and inactivated states . Here we present high-resolution structures of the model bacterial sodium channel NaAb with the analogous gating-charge mutations, which have similar functional effects as in the human channels. The R2G and R3G mutations have no effect on the backbone structures of the voltage sensor, but they create an aqueous cavity near the hydrophobic constriction site that controls gating charge movement through the voltage sensor. The R3G mutation extends the extracellular aqueous cleft through the entire length of the activated voltage sensor, creating an aqueous path through the membrane. Conversely, molecular modelling shows that the R2G mutation creates a continuous aqueous path through the membrane only in the resting state. Crystal structures of NaAb(R2G) in complex with guanidinium define a potential drug target site. Molecular dynamics simulations illustrate the mechanism of Na permeation through the mutant gating pore in concert with conformational fluctuations of the gating charge R4. Our results reveal pathogenic mechanisms of periodic paralysis at the atomic level and suggest designs of drugs that may prevent ionic leak and provide symptomatic relief from hypokalaemic and normokalaemic periodic paralysis.

PubMed: 29769724
DOI: 10.1038/s41586-018-0120-4

Experimental method

X-RAY DIFFRACTION (2.9 Å)