| Autor: |
Valentina Tereshko, Anna S. Levine, Luigi Di Costanzo, William F. DeGrado, Rudresh Acharya, Vikas Nanda, Cinque Soto, Amanda L. Stouffer, Steven Stayrook, David Salom |
| Přispěvatelé: |
Stouffer, A. L., Acharya, R., Salom, D., Levine, A. S., DI COSTANZO, Luigi, Soto, C. S., Tereshko, V., Nanda, V., Stayrook, S., Degrado, W. F. |
| Jazyk: |
angličtina |
| Rok vydání: |
2008 |
| Předmět: |
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| Popis: |
Until recently, the pH-gated proton channel of influenza A virus, M2, was effectively targeted by amantadine-based antivirals, but resistance to these drugs is now widespread. Two groups now present structural studies of M2 proton channel. Jason Schnell and James Chou determine the structure of a 38-residue segment of M2, in complex with rimantadine, by NMR spectroscopy. Amanda Stouffer et al. determined the crystal structure of a 25-residue fragment of M2, with and without amantadine, using X-ray diffraction. Strikingly, the resulting structures suggest two very different mechanisms by which the drug inhibits the channel. The proposed mechanisms are discussed by Christopher Miller in an accompanying News & Views article. A vital component of influenza A virus' replication machinery is the M2 proton channel. Until recently, M2 was effectively targeted by amantadane-based antivirals, but resistance to these drugs is now so widespread that they have become ineffective. In the second of two related manuscripts, the crystal structure of a 25-residue fragment of M2, both with and without amantadine, is described. It is concluded that a single amantadine molecule binds in the centre of the M2 tetramer to physically occlude the pore. The M2 protein from influenza A virus is a pH-activated proton channel that mediates acidification of the interior of viral particles entrapped in endosomes. M2 is the target of the anti-influenza drugs amantadine and rimantadine; recently, resistance to these drugs in humans, birds and pigs has reached more than 90% (ref. 1). Here we describe the crystal structure of the transmembrane-spanning region of the homotetrameric protein in the presence and absence of the channel-blocking drug amantadine. pH-dependent structural changes occur near a set of conserved His and Trp residues that are involved in proton gating2. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses3,4. Binding of amantadine physically occludes the pore, and might also perturb the pKa of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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