Pentapeptide repeat protein for resistance against quinolones, MfpA
Mycobacterium tuberculosis (bacteria)
Tuberculosis is one of the most common infectious diseases. It is estimated that almost one-third of the world's population is infected with it. It claims 2 million deaths each year. Fortunately in most cases the infection does not progress to an active disease, but if this happens and the patient is left without treatment, he or she has about 50% chance of survival. At the same time inadequate treatment regimen leads to drug resistance, thus impeding the efforts for eliminating this global health problem. Tuberculosis is caused and transmitted by the aerobic bacterium Mycobacterium tuberculosis. A major group of anti-biotics used in the fight against it are the quinolones. They are powerful drugs showing relatively few side-effects. They exert their anti-bacterial properties by inhibiting DNA gyrase activity, thus preventing DNA replication and effectively stopping the development of the disease. One of the resistance mechanisms that occurs in Mycobacterium tuberculosis is the expression of MfpA-encoded protein, a member of the 'pentapeptide repeat' protein family. The name of the family comes from the fact that every fifth amino acid is either a leucine or phenylalanine.
Here we can see the structure of the MfpA dimer, which is found to be the stable form in both solutions and crystals. The two monomers in the dimer are connected by non-covalent interaction between their C-terminal alpha-helices. Each of them resembles an almost perfect spring of a right-handed beta-helix. The helix forms 8 complete coils stabilized by inter-coil hydrogen bonds. Each coil is realized by 20 residues, with 4.8 angstroms distance to the neighboring ones. The dimer itself is about 100 angstroms long, with diameter changing from 27 to 18 angstroms as the dimer interface is approached. The total charge of -10 is not evenly distributed but rather concentrated on two sides only. Taking into account this electrostatic potential as well as the size and shape of the peptide dimer we can easily find an explanation for its inhibition activity. Exhibiting physical properties very similar to a 30-base duplex DNA , MfpA competes with it by binding to DNA gyrase. Drugs that can suppress expression of MfpA or disturb the formation of the dimer will be likely candidates to assist in overcoming this antibiotics resistance.
Protein Data Bank (PDB)
Hegde, S.S. Vetting, M.W. Roderick, S.L. Mitchenall, L.A. Maxwell, A. Takiff, H.E. Blanchard, J.S.; "A Fluroquinolone Resistance Protein from Mycobacterium Tuberculosis that Mimics DNA"; Science; (2005) 308:1480-1483. PubMed:15933203
author: Rossen Apostolov