Structural Biochemistry, Binding of the Drug Amantadine to the Proton Channels of the M2 Protein in the Influenza Virus

Overall Idea

The biochemical structure of the M2 proton channel in influenza A was uncovered with the techniques of Nuclear Magnetic Resonance (NMR) for the closed state and X-ray crystallography for the open state. It is believed that the sole inhibitor-binding site shown by the X-ray structure to be directly in the center of the channel is responsible for binding to the drug amantadine, even though NMR revealed the possibility of the exterior binding of four additional inhibitors on the outside of the channel under certain states.

Protein M2 Proton Channel Structure and Importance

The M2 protein is a 97-residue protein that is made up of 23 amino acids; it is a single-pass membrane protein that has all of the N-terminus’s orientated to the outside of the cell. Inside of the cell is a 19 residue transmembrane domain (M2TM) and a 54-residue tail. It is the M2TM, which is the target of the anti-influenza drugs amantadine and rimantadine. The structure of these residues was solved using a combination of X-ray crystallography and NMR techniques; both techniques support a semi-symmetric tetramer proton channel, the section inside the cell membrane coiling in a leftward orientation. The structural determination of this channel differs between these two methods in regards to the bound inhibitor position. Even though both methods suggest similar hot-spots for possible binding sites inside and on the outside of the channel, X-ray crystallography indicates a amantadine binding site in the central pore of the channel whereas NMR indicates four rimantadine binding sites on the surface outside of the channel.
It is important to know the structure of this proton channel, the location of the binding sites and their functionality in order to better assess how the anti-influenza drugs bind to the virus protein and carry out their functions. Most strain of influenza have recently developed a resistance to these two drugs, with a large 97% of people having some of the virus containing a specific Ser31Asn substitution which makes the virus highly resistant to these drugs. Therefore it is vital to further prove the structure of this proton channel’s binding sites in order to fully realize how the drug binds to the channel and how resistance to these drugs has developed. Once these facts are determined, scientists can attempt to uncover other compounds that might inhibit the M2 protein channel as these drugs once did.

New NMR Study Discoveries

New solid state NMR data looking at a closed M2 channel revealed a central binding site with high affinity for amantadine with four outer binding sites with low affinity for the drug. This confirmed earlier X-ray crystallography and NMR data as well as exposing that the main binding site for amantadine is most likely in the central pore of the M2 channel. Although the prominence of a single central inhibition is assumed, it is quite possible that there is a dual inhibition mechanism, so further scientific research is necessary. One additional thought is that the secondary inhibitor sites on the outside of the channel might play a greater role in drug binding for the mutant drug-resistant influenza virus which is now present in 97% of people who are tested.

[1]

Footnotes

• ↑ Kozakov, Dima. Chuang, Gwo-Yu. Beglov, Dmitri. Vajda, Sandor. 2010 September ; “Where does amantadine bind to the influenza virus M2 proton channel?” Trends Biochem Sci. 35(9): 471-475. doi: 10.1016/j.tibs.2010.03.2006.

Where this page came from

This page was imported from Wikibooks. From “Structural Biochemistry” on Wikibooks, by its contributors, under CC BY-SA 4.0. Changed here: set as a page; navigation and edit links left out; each image under its own licence, credited in its caption.

Nobody has written it yet — it is the source material at a new address, which is why search engines are asked to skip it and why no one earns from it. It is up for grabs: take it on, and it is yours to rewrite and to earn from.