Protonation of Histidine and Histidine−Tryptophan Interaction in the Activation of the M2 Ion Channel from Influenza A Virus

Okada, Atsushi; Miura, Tadao; Takeuchi, Hideo

doi:10.1021/bi0028441

Cited by 216 publications

(322 citation statements)

References 44 publications

(89 reference statements)

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“…In addition, modes specific to the tryptophan six-membered ring, W16, W13 and W7 (1,345 cm −1 ), undergo frequency shifts of −2, −4 and +3 respectively upon metal complex formation. A similar pattern of intensity changes and intensity inversion has been previously characterized for cation-tryptophan π interactions in both protein and small-molecule model systems 13 . It is notable that the magnitude of the intensity changes observed for CusF upon metal coordination is considerably greater than what has been previously reported for cation-π interactions and that these changes are accompanied by small tryptophan wavelength shifts.…”

supporting

confidence: 76%

Cu(I) recognition via cation-π and methionine interactions in CusF

et al. 2007

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Methionine-rich motifs have an important role in copper trafficking factors, including the CusF protein. Here we show that CusF uses a new metal recognition site wherein Cu(I) is tetragonally displaced from a Met 2 His ligand plane toward a conserved tryptophan. Spectroscopic studies demonstrate that both thioether ligation and strong cation-π interactions with tryptophan stabilize metal binding. This novel active site chemistry affords mechanisms for control of adventitious metal redox and substitution chemistry.In recent years, metal-specific gene regulatory and cation-trafficking proteins have been isolated and demonstrate metal binding motifs with unprecedented coordination chemistry tailored to their function 1 . For example, the CXXC sequence, found in cytosolic copper chaperones and trafficking proteins, provides for facile Cu(I) transfer via low-coordinationnumber anionic intermediates 1,2 . Extracellular or periplasmic copper trafficking domains, however, function in environments that are more oxidizing than the cytosol and frequently have less well understood methionine-rich sequences 3-8 . The cus operon encodes a bacterial copper homeostasis system with several methionine-motif proteins 5,9,10 , including the periplasmic protein CusF, which is thought to serve as copper chaperone or regulator 5,6 . CusF binds Cu(I) in vitro 11 , and a methionine-rich Cu(I) site was proposed 6 based on an apo-CusF structure and NMR chemical shift data. Here we show that metal recognition in CusF involves a strong interaction between a cationic Cu(I)-thioether/imidazole center and the aromatic ring of tryptophan. To our knowledge, such cation-π interactions have not been reported for transition metal receptors or metalloenzyme active sites.Correspondence should be addressed to T.V.O. (t-ohalloran@northwestern.edu). 6 These authors contributed equally to this work.Published online at http://www.nature.com/naturechemicalbiology Reprints and permissions information is available online at

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supporting

confidence: 76%

Cu(I) recognition via cation-π and methionine interactions in CusF

et al. 2007

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“…1 A and B), which H-bonds to the N ε of each His37 residue. This dimer is well positioned to mediate a π-cation interaction (38) between charged His37 residues and the electron-rich faces of Trp41 residues. Lastly, the exit cluster ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus

Acharya

Carnevale

Fiorin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

246

520

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The M2 proton channel from influenza A virus is an essential protein that mediates transport of protons across the viral envelope. This protein has a single transmembrane helix, which tetramerizes into the active channel. At the heart of the conduction mechanism is the exchange of protons between the His37 imidazole moieties of M2 and waters confined to the M2 bundle interior. Protons are conducted as the total charge of the four His37 side chains passes through 2 þ and 3 þ with a pK a near 6. A 1.65 Å resolution X-ray structure of the transmembrane protein (residues 25-46), crystallized at pH 6.5, reveals a pore that is lined by alternating layers of sidechains and well-ordered water clusters, which offer a pathway for proton conduction. The His37 residues form a box-like structure, bounded on either side by water clusters with wellordered oxygen atoms at close distance. The conformation of the protein, which is intermediate between structures previously solved at higher and lower pH, suggests a mechanism by which conformational changes might facilitate asymmetric diffusion through the channel in the presence of a proton gradient. Moreover, protons diffusing through the channel need not be localized to a single His37 imidazole, but instead may be delocalized over the entire His-box and associated water clusters. Thus, the new crystal structure provides a possible unification of the discrete site versus continuum conduction models.ion channels | M2 proton channel | membrane proteins | water clusters | histidine protonation W ater molecules confined at interfaces or in cavities behave differently from those in the bulk. Studies of water clusters have shed light not only on their fundamental properties (1-4) but also on the mechanism employed by various nano-bio systems to fine-tune water and proton transport (5-9). A relevant example from biology is the M2 protein of the influenza A virus (10, 11), which is the target of the influenza drugs amantadine and rimantadine (12-17). Tetrameric M2 (18) transports protons across the viral envelope to acidify the virion interior and trigger uncoating of the viral RNA prior to fusion of the viral envelope with the endosomal bilayer (19). M2 is one of the smallest bona fide channel/transporter proteins (96 residues), capable of pHdependent activation and highly selective conduction of protons vs. other ions (20)(21)(22)(23)(24)(25). A narrow pore leads to the highly conserved His37 and Trp41 residues (16,17,(26)(27)(28)(29), which are respectively responsible for proton selectivity (30) and asymmetry in the magnitude of conductance when the proton gradient is reversed (31). Thus the control of proton diffusion across the membrane relies on the ability of the imidazole moieties of His37 to accept and store protons from water molecules in the pore.An M2 peptide (residues 22-46), slightly longer than the transmembrane domain (32), associates into a functional four-helix bundle (33). Solid state 15 N nuclear magnetic resonance (ssNMR) experiments indicate that the first protons ...

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“…Cation-pi interactions between tryptophan and imidazolium have been observed in numerous systems. (47)(48)(49).…”

Section: Effect Of the H29a And W163a Substitutions On Thdp Binding mentioning

confidence: 99%

Probing the Active Center of Benzaldehyde Lyase with Substitutions and the Pseudosubstrate Analogue Benzoylphosphonic Acid Methyl Ester

et al. 2008

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Benzaldehyde lyase (BAL) catalyzes the reversible cleavage of (R)-benzoin to benzaldehyde utilizing thiamin diphosphate and Mg 2+ as cofactors. The enzyme is important for the chemoenzymatic synthesis of a wide range of compounds via its carboligation reaction mechanism. In addition to its principal functions, BAL can slowly decarboxylate aromatic amino acids such as benzoylformic acid. It is also intriguing mechanistically due to the paucity of acid-base residues at the active center that can participate in proton transfer steps thought to be necessary for these types of reactions. Here methyl benzoylphosphonate, an excellent electrostatic analogue of benzoylformic acid, is used to probe the mechanism of benzaldehyde lyase. The structure of benzaldehyde lyase in its covalent complex with methyl benzoylphosphonate was determined to 2.49 Å (Protein Data Bank entry 3D7K) and represents the first structure of this enzyme with a compound bound in the active site. No large structural reorganization was detected compared to the complex of the enzyme with thiamin diphosphate. The configuration of the predecarboxylation thiamin-bound intermediate was clarified by the structure. Both spectroscopic and X-ray structural studies are consistent with inhibition resulting from the binding of MBP to the thiamin diphosphate in the active centers. We also delineated the role of His29 (the sole potential acid-base catalyst in the active site other than the highly conserved Glu50) and Trp163 in cofactor activation and catalysis by benzaldehyde lyase.

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Protonation of Histidine and Histidine−Tryptophan Interaction in the Activation of the M2 Ion Channel from Influenza A Virus

Cited by 216 publications

References 44 publications

Cu(I) recognition via cation-π and methionine interactions in CusF

Cu(I) recognition via cation-π and methionine interactions in CusF

Structure and mechanism of proton transport through the transmembrane tetrameric M2 protein bundle of the influenza A virus

Probing the Active Center of Benzaldehyde Lyase with Substitutions and the Pseudosubstrate Analogue Benzoylphosphonic Acid Methyl Ester

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