PDBsum entry 3bkd

Viral protein, membrane protein

PDB id: 3bkd

Contents

Protein chains

(+ 2 more) 26 a.a.

Ligands

BOG ×6

PEG ×6

Metals

_CL ×2

Waters ×39

PDB id:

3bkd

Name:

Viral protein, membrane protein

Title:

High resolution crystal structure of transmembrane domain of m2 protein

Structure:

Transmembrane domain of matrix protein m2. Chain: a, b, c, d, e, f, g, h. Fragment: residues 22-46. Engineered: yes

Source:

Synthetic: yes. Other_details: chemically synthesized. Transmembrane domain of m2 protein from influenza a virus

Resolution:

2.05Å R-factor: 0.222 R-free: 0.269

Authors:

A.L.Stouffer,R.Acharya,D.Salom

Key ref:

A.L.Stouffer et al. (2008). Structural basis for the function and inhibition of an influenza virus proton channel. Nature, 451, 596-599. PubMed id: 18235504 DOI: 10.1038/nature06528

Date:

06-Dec-07 Release date: 29-Jan-08

Protein chains

Q9Q0P0  (Q9Q0P0_9INFA) -  Matrix protein 2 from Influenza A virus

Seq: 97 a.a.

Struc: 26 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1038/nature06528

Nature 451:596-599 (2008)

PubMed id: 18235504

Structural basis for the function and inhibition of an influenza virus proton channel.

A.L.Stouffer, R.Acharya, D.Salom, A.S.Levine, L.Di Costanzo, C.S.Soto, V.Tereshko, V.Nanda, S.Stayrook, W.F.DeGrado.

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 gating. The drug-binding site is lined by residues that are mutated in amantadine-resistant viruses. 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.

Selected figure(s)

Figure 2.
Figure 2: Asymmetric structure of the C-terminal His/Trp gate of M2TM. a, Crystal structure of the tetramer viewed from the inside of the virus, with the helices labelled A–D. b, In the C–D interface, Asp 44 and Arg 45 form a salt bridge, and His 37 and Trp 41 engage in an inter-subunit edge-on aromatic interaction. c, These residues do not interact at the A–B interface.

Figure 4.
Figure 4: Minimal mechanism of activation and conductance through the channel. Two helices of the tetramer and one protonation event are shown for simplicity.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2008, 451, 596-599) copyright 2008.

Figures were selected by an automated process.