1. Department of Biochemistry and Biophysics, School of Medicine,
2. Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3. Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA
4. Present addresses: Laboratory of Organic Chemistry, ETH Hönggerberg, 8093 Zurich, Switzerland (A.L.S.); Polgenix, Inc., Cleveland, Ohio 44106, USA (D.S); Box 2525, Brown University, Providence, Rhode Island 02912, USA (A.S.L.); Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA (V.N.).
5. These authors contributed equally to this work.

Correspondence to: William F. DeGrado^1,2 Correspondence and requests for materials should be addressed to W.F.D. (Email: wdegrado@mail.med.upenn.edu).

Abstract

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 viruses^{3, 4}. Binding of amantadine physically occludes the pore, and might also perturb the pK_a of the critical His residue. The structure provides a starting point for solving the problem of resistance to M2-channel blockers.

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