Sandbox 1666

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Function of Protein

This protein is produced in bacteria, more specifically E. coli. CTX-M Beta-Lactamase is produced in bacteria which causes drug resistance in B-lactam antibiotics, also known as penicillin. It attacks the amide bond in the lactam anitbiotics, which causes deacylation to occur. is the overall structure of CTX-M Beta-Lactamase.

Known substrates of this protein are ampicillin and cefotaxime. These are key determinants of resistance to antibiotics. This also determines what drugs are susceptible of bacteria that harbor the enzymes.

Biological Relevance and Broader Implications

Since Beta-Lactam antibiotics are used very often in antimicrobial therapy to treat bacterial infections, bacterial resistance often ocurrs. This protein, CTX-M Beta-Lactamase, causes this drug resistance, which is a problem. It is a problem because if we can understand it better, we can change the way we treat to fight off the bacteria better.

There have been several inhibitor-resistant variants that mutations have risen from. More specifically one of them being K23YR. This mutation causes a 1500-fold decrease in the cefotaxime and a 5-fold increase in the Kcat for ampicillin. This makes it become a good penicillinase, but a poor cephalosporinase due to slow acylation. The mutation of this will lead to the enzyme being inactivated, making the drug resistance not work efficiently.

The research of this protein is very significant because it has a direct clinical application.

Important Amino Acids

An important ligand of this protein is , which is the only ligand in this protein. GOL helps with stability of this protein. The consists of the amino acids Ser70 (green), Ser130 (blue), and Lys73 (pink). Ser70 interacts with the oxygen on the ampicillin, and it is also cross-linked with clavulanic acid. Ser130 is also cross-linked with clavulanic acid and interacts with the ligand through hydrogen bonds. Lys73 interacts with the ligand through hydrogen bonds used to lower the pka value of the hydroxyl group. Lys234 also plays an important role in the proton transfer during the catalysis of the antibiotics. An active site residue of this protein that causes deacylation to occur is Glu166. This residue activates a catalytic water molecule.

Structural highlights

This protein has eight chains. Each chain has eleven separate alpha helices and nine separate beta sheets. Some of the chains bind to GOL to help with stability. Within each chain, there are two of the catalytic amino acid within helix three. The last catalytic amino acid is located in helix seven. Both of these helices form important interactions with the ligands because of those catalytic amino acids, which have been highlighted here.

Other Important Features