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Observing intramolecular motion of ligand gated ion channel in real time

Establishment of X-ray technology for allosteric drug design

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Graduate School of Frontier Sciences
2014/09/26

A research group led by Professor Yuji Sasaki (Graduate School of Frontier Sciences, the University of Tokyo) has for the first time succeeded in the real-time visual monitoring in three dimensions of intramolecular motions of nicotinic acetylcholine receptor (nAChR) at the single-molecule level with atomic scale and 100 µs time resolution. nAChR is the focus of intense research for its role in regulating muscle movement, memory and learning.

DXT measurements of AChBP (acetylcholine binding protein) and nAChR. (a-b): Schematic of the immobilisation of gold nanocrystals on AChBP (a) and nAChR (b). (c): Schematic of the tilting (θ) and twisting (χ) motions observed by DXT.

© 2014 Hiroshi Sekiguchi.
DXT measurements of AChBP (acetylcholine binding protein) and nAChR. (a-b): Schematic of the immobilisation of gold nanocrystals on AChBP (a) and nAChR (b). (c): Schematic of the tilting (θ) and twisting (χ) motions observed by DXT.

The research group distinguish the characteristic intramolecular motion of homo- pentameric protein from hetro- pentameric protein by single molecule analysis of diffracted X-ray tracking (DXT). The DXT method utilized in this study is a powerful method for extracting intramolecular motion of a variety of protein molecules and enables the observation of all principal protein components of a single molecule without significant preparatory manipulation. Further, the capture of information about intramolecular dynamics could contribute greatly to the future development of allosteric drugs without side-effects.

This research was carried out with the collaboration of Dr. Hiroshi Sekiguchi (Japan Synchrotron Radiation Research Institute), Dr. Tai Kubo (National Institute of Advanced Industrial Science and Technology) Prof. Atsuo Miyazawa (University of Hyogo), and Prof. Masato Okada (Graduate School of Frontier Sciences, the University of Tokyo).

Press release (Japanese)

Paper

Hiroshi Sekiguchi, Yasuhito Suzuki, Yuri Nishino, Suzuko Kobayashi, Yoshiko Shimoyama, Weiyan Cai, Kenji Nagata, Masato Okada, Kouhei Ichiyanagi, Noboru Ohta, Naoto Yagi, Atsuo Miyazawa, Tai Kubo, Yuji C Sasaki,
“Real Time Ligand-Induced Motion Mappings of AChBP and nAChR using X-ray Single Molecule Tracking”,
Scientific Reports Online Edition: 2014/9/16 (Japan time), doi: 10.1038/srep06384.
Article link

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Graduate School of Frontier Sciences

Department of Advanced Materials Science, Transdisciplinary Sciences, Graduate School of Frontier Sciences

Y. C. Sasaki Laboratory, Department of Advanced Materials Science, Transdisciplinary Sciences, Graduate School of Frontier Sciences

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