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  Structure and mechanism of the influenza A M2(18-60) dimer of dimers.

Andreas, L. B., Reese, M., Eddy, M. T., Gelev, V., Ni, Q. Z., Miller, E. A., et al. (2015). Structure and mechanism of the influenza A M2(18-60) dimer of dimers. Journal of the American Chemical Society, 137(47), 14877-14886. doi:10.1021/jacs.5604802.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-9221-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-9225-C
Genre: Journal Article

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Andreas, L. B.1, Author              
Reese, M., Author
Eddy, M. T., Author
Gelev, V., Author
Ni, Q. Z., Author
Miller, E. A., Author
Emsley, L., Author
Pintacuda, G., Author
Chou, J. J., Author
Griffin, R. G., Author
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1Research Group of Solid State NMR Spectroscopy-2, MPI for Biophysical Chemistry, Max Planck Society, ou_2396693              

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 Abstract: We report a magic angle spinning (MAS) NMR structure of the drug-resistant S31N mutation of M2(18-60) from Influenza A. The protein was dispersed in diphytanoyl-sn-glycero-3-phosphocholine lipid bilayers, and the spectra and an extensive set of constraints indicate that M2(18-60) consists of a dimer of dimers. In particular, similar to 280 structural constraints were obtained using dipole recoupling experiments that yielded well-resolved C-13-N-15, C-13-C-13, and H-1-N-15 2D, 3D, and 4D MAS spectra, all of which show cross-peak doubling. Interhelical distances were measured using mixed N-15/C-13 labeling and with deuterated protein, MAS at omega(r)/2 pi = 60 kHz, omega(0H)/2 pi = 1000 MHz, and 11-1 detection of methyl methyl contacts. The experiments reveal a compact structure consisting of a tetramer composed of four transmembrane helices, in which two opposing helices are displaced and rotated in the direction of the membrane normal relative to a four-fold symmetric arrangement, yielding a two-fold symmetric structure. Side chain conformations of the important gating and pH-sensing residues W41 and H37 are found to differ markedly from four-fold symmetry. The rmsd of the structure is 0.7 angstrom for backbone heavy atoms and 1.1 A for all heavy atoms. This two-fold symmetric structure is different from all of the previous structures of M2, many of which were determined in detergent and/or with shorter constructs that are not fully active. The structure has implications for the mechanism of H+ transport since the distance between His and Trp residues on different helices is found to be short. The structure also exhibits two-fold symmetry in the vicinity of the binding site of adamantyl inhibitors, and steric constraints may explain the mechanism of the drug-resistant S31N mutation.

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Language(s): eng - English
 Dates: 2015-07-282015
 Publication Status: Published in print
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 Rev. Method: Peer
 Identifiers: DOI: 10.1021/jacs.5604802
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Title: Journal of the American Chemical Society
Source Genre: Journal
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Pages: - Volume / Issue: 137 (47) Sequence Number: - Start / End Page: 14877 - 14886 Identifier: -