5ttc

From Proteopedia

XFEL structure of influenza A M2 wild type TM domain at high pH in the lipidic cubic phase at room temperature

Structural highlights

5ttc is a 1 chain structure with sequence from Influenza A virus (A/Hickox/1940(H1N1)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.4Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

M2_I40A0 Forms a proton-selective ion channel that is necessary for the efficient release of the viral genome during virus entry. After attaching to the cell surface, the virion enters the cell by endocytosis. Acidification of the endosome triggers M2 ion channel activity. The influx of protons into virion interior is believed to disrupt interactions between the viral ribonucleoprotein (RNP), matrix protein 1 (M1), and lipid bilayers, thereby freeing the viral genome from interaction with viral proteins and enabling RNA segments to migrate to the host cell nucleus, where influenza virus RNA transcription and replication occur. Also plays a role in viral proteins secretory pathway. Elevates the intravesicular pH of normally acidic compartments, such as trans-Golgi network, preventing newly formed hemagglutinin from premature switching to the fusion-active conformation.

Publication Abstract from PubMed

The M2 proton channel of influenza A is a drug target that is essential for the reproduction of the flu virus. It is also a model system for the study of selective, unidirectional proton transport across a membrane. Ordered water molecules arranged in "wires" inside the channel pore have been proposed to play a role in both the conduction of protons to the four gating His37 residues and the stabilization of multiple positive charges within the channel. To visualize the solvent in the pore of the channel at room temperature while minimizing the effects of radiation damage, data were collected to a resolution of 1.4 A using an X-ray free-electron laser (XFEL) at three different pH conditions: pH 5.5, pH 6.5, and pH 8.0. Data were collected on the Inwardopen state, which is an intermediate that accumulates at high protonation of the His37 tetrad. At pH 5.5, a continuous hydrogen-bonded network of water molecules spans the vertical length of the channel, consistent with a Grotthuss mechanism model for proton transport to the His37 tetrad. This ordered solvent at pH 5.5 could act to stabilize the positive charges that build up on the gating His37 tetrad during the proton conduction cycle. The number of ordered pore waters decreases at pH 6.5 and 8.0, where the Inwardopen state is less stable. These studies provide a graphical view of the response of water to a change in charge within a restricted channel environment.

XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction.,Thomaston JL, Woldeyes RA, Nakane T, Yamashita A, Tanaka T, Koiwai K, Brewster AS, Barad BA, Chen Y, Lemmin T, Uervirojnangkoorn M, Arima T, Kobayashi J, Masuda T, Suzuki M, Sugahara M, Sauter NK, Tanaka R, Nureki O, Tono K, Joti Y, Nango E, Iwata S, Yumoto F, Fraser JS, DeGrado WF Proc Natl Acad Sci U S A. 2017 Aug 23. pii: 201705624. doi:, 10.1073/pnas.1705624114. PMID:28835537^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Thomaston JL, Woldeyes RA, Nakane T, Yamashita A, Tanaka T, Koiwai K, Brewster AS, Barad BA, Chen Y, Lemmin T, Uervirojnangkoorn M, Arima T, Kobayashi J, Masuda T, Suzuki M, Sugahara M, Sauter NK, Tanaka R, Nureki O, Tono K, Joti Y, Nango E, Iwata S, Yumoto F, Fraser JS, DeGrado WF. XFEL structures of the influenza M2 proton channel: Room temperature water networks and insights into proton conduction. Proc Natl Acad Sci U S A. 2017 Aug 23. pii: 201705624. doi:, 10.1073/pnas.1705624114. PMID:28835537 doi:http://dx.doi.org/10.1073/pnas.1705624114