An Improved Method for Modeling Voltage-Gated Ion Channels at Atomic Accuracy Applied to Human Cav Channels
Voltage-gated ion channels (VGICs) are associated with hundreds of human diseases. To date, 3D structural models of human VGICs have not been reported. We developed a 3D structural integrity metric to rank the accuracy of all VGIC structures deposited in the PDB. The metric revealed inaccuracies in...
Saved in:
Published in | Cell reports (Cambridge) Vol. 23; no. 5; pp. 1399 - 1408 |
---|---|
Main Authors | , |
Format | Journal Article |
Language | English |
Published |
Elsevier Inc
01.05.2018
Elsevier |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Voltage-gated ion channels (VGICs) are associated with hundreds of human diseases. To date, 3D structural models of human VGICs have not been reported. We developed a 3D structural integrity metric to rank the accuracy of all VGIC structures deposited in the PDB. The metric revealed inaccuracies in structural models built from recent single-particle, non-crystalline cryo-electron microscopy maps and enabled the building of highly accurate homology models of human Cav channel α1 subunits at atomic resolution. Human Cav Mendelian mutations mostly located to segments involved in the mechanism of voltage sensing and gating within the 3D structure, with multiple mutations targeting equivalent 3D structural locations despite eliciting distinct clinical phenotypes. The models also revealed that the architecture of the ion selectivity filter is highly conserved from bacteria to humans and between sodium and calcium VGICs.
[Display omitted]
•Core residue contact surface area is quantitative structure accuracy metric•Refine low-resolution X-ray and cryo-EM structures to atomic resolution with metric•Identify/correct inaccuracies in mammalian voltage-gated ion channel structure•Metric-refined channel models illuminate mechanism and disease-causing mutations
Martinez-Ortiz et al. develop an accuracy metric for structural models of voltage-gated ion channels based on the conservation of a core functional cluster of amino acids. The significance of the method is its ability to reveal and correct subtle modeling errors and refine low-resolution VGICs to atomic accuracy. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2018.04.024 |