Refinement of a Cryo-EM Structure of HERG: Bridging Structure and Function

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2021 Jan 21

PMID 33476597

Citations 5

Authors

Hanif M Khan

Jiqing Guo

Henry J Duff

D Peter Tieleman

Sergei Y Noskov

Affiliations

Soon will be listed here.

Abstract

The human-ether-a-go-go-related gene (hERG) encodes the voltage-gated potassium channel (KCNH2 or Kv11.1, commonly known as hERG). This channel plays a pivotal role in the stability of phase 3 repolarization of the cardiac action potential. Although a high-resolution cryo-EM structure is available for its depolarized (open) state, the structure surprisingly did not feature many functionally important interactions established by previous biochemical and electrophysiology experiments. Using molecular dynamics flexible fitting (MDFF), we refined the structure and recovered the missing functionally relevant salt bridges in hERG in its depolarized state. We also performed electrophysiology experiments to confirm the functional relevance of a novel salt bridge predicted by our refinement protocol. Our work shows how refinement of a high-resolution cryo-EM structure helps to bridge the existing gap between the structure and function in the voltage-sensing domain (VSD) of hERG.

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