Structural biology. The flu's proton escort

Abstract

A flurry of structural data provides sometimes conflicting insights into the M2 proton channel.

Figure 1. Flu in detail

The high-resolution crystal structure ( 8) of M2TM ( A) is similar to spectroscopic structures of longer ( B) constructs solved by SSNMR (5), (red), solution NMR ( 12) (light blue) or EPR ( 15) (yellow). The high-resolution structure (A) at intermediate pH shows a proton-conduction path consisting of layers of water molecules interleaved between the pore-lining side chains. The His³⁷ residues polarize intervening water molecules, encouraging entry of protons from the exterior. Water molecules are well positioned to increase the basicity of the N_δ atoms of His³⁷ by simultaneously forming hydrogen bonds to the carbonyl of Gly³⁴. Interactions between N_ε and the electron-rich face of Trp⁴¹ further stabilize the His-box. In the doubly charged state, this interaction is mediated by an intervening dimer of water molecules, which are weakened or converted to direct side-chain–side-chain interactions ( 8) in the neutral state. Additional water clusters toward the interior provide indirect charge stabilization and complete an exit pathway. (C) Low protonation (PDB ID codes: 2KQT, green; 3LBW, purple) ( 11, 16) versus (D) greater protonation (PDB ID code 3BKD, blue) ( 8) show that increasing protonation of the His box/water cluster causes the pore to contract on the exterior and expand near the interior, promoting movement of protons past the Trp⁴¹ gate into the interior of the virus ( 11). The structure of the C-terminal amphiphilic helix of Sharma et al. seen in (E) differs markedly from that of Schnell and Chou ( 12) in (F) but resembles the EPR model of Nguyen, Howard, and co-workers (G) ( 15).