Nuclear magnetic resonance structural studies of a potassium channel-charybdotoxin complex

Liping Yu; Chaohong Sun; Danying Song; Jianwei Shen; Nan Xu; Angelo Gunasekera; Philip J Hajduk; Edward T Olejniczak

doi:10.1021/bi051656d

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Nuclear magnetic resonance structural studies of a potassium channel-charybdotoxin complex

Journal article

Peer reviewed

Nuclear magnetic resonance structural studies of a potassium channel-charybdotoxin complex

Liping Yu, Chaohong Sun, Danying Song, Jianwei Shen, Nan Xu, Angelo Gunasekera, Philip J Hajduk and Edward T Olejniczak

Biochemistry (Easton), Vol.44(48), pp.15834-15841

12/06/2005

DOI: 10.1021/bi051656d

PMID: 16313186

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Abstract

Ion channels play critical roles in signaling processes and are attractive targets for treating various diseases. Here we describe an NMR-based strategy for structural analyses of potassium channel-ligand complexes using KcsA (residues 1-132, with six mutations to impart toxin binding and to mimic the eukaryotic hERG channel). Using this approach, we determined the solution structure of KcsA in complex with the high-affinity peptide antagonist charybdotoxin. The structural data reveal how charybdotoxin binds to the closed form of KcsA and makes specific contacts with the extracellular surface of the ion channel, resulting in pore blockage. This represents the first direct structural information about an ion channel complexed to a peptide antagonist and provides an experimental framework for understanding and interpreting earlier mutational analyses. The strategy presented here overcomes many of the limitations of conventional NMR approaches to helical membrane protein structure determination and can be applied in the study of the binding of druglike molecules to this important class of proteins.

Amino Acid Sequence

Bacterial Proteins - chemistry

Bacterial Proteins - genetics

Charybdotoxin - chemistry

Crystallization

DNA Mutational Analysis

Electron Spin Resonance Spectroscopy

Models, Molecular

Molecular Sequence Data

Nuclear Magnetic Resonance, Biomolecular

Peptides - chemistry

Potassium Channels - chemistry

Potassium Channels - genetics

Scorpion Venoms - chemistry

Sequence Alignment

Shaker Superfamily of Potassium Channels

Details

Title: Subtitle: Nuclear magnetic resonance structural studies of a potassium channel-charybdotoxin complex
Creators: Liping Yu - Abbott (United States)
Chaohong Sun - Abbott (United States)
Danying Song - Abbott (United States)
Jianwei Shen
Nan Xu - Abbott (United States)
Angelo Gunasekera - Abbott (United States)
Philip J Hajduk - Abbott (United States)
Edward T Olejniczak - Abbott (United States)
Resource Type: Journal article
Publication Details: Biochemistry (Easton), Vol.44(48), pp.15834-15841
DOI: 10.1021/bi051656d
PMID: 16313186
NLM abbreviation: Biochemistry
ISSN: 0006-2960
eISSN: 1520-4995
Language: English
Date published: 12/06/2005
Academic Unit: Biochemistry and Molecular Biology; Medicine Administration
Record Identifier: 9984627214702771

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