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This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439.

Penicillin binding protein/lactivicin (inhibitor) (2jch)

by Tyler Carpenter, Samuel Pierce, Hyunjoon Choi, Anton El Khoury and Tiankai Zhang

Student Projects for UMass Chemistry 423 Spring 2016 <StructureSection load='2jch' size='350' side='right' caption='Key player in cell rescue from the imminent death (2jch)' scene='48/483886/Rainbow/1'>

Introduction

Every bacteria wants to live. Every bacteria wants to reproduce. To achieve both, bacteria need some sort of protection that will maintain the structure inside and will protect it from outside dangers. This protection is called cell wall, that primarily consists of a polymer that is called peptidoglycan. This compound can be synthesized only with the help of penicillin binding proteins (PBPs) , which are the target of this article (the name basically comes from a way it was discovered). PBP serves as a catalyst in the final stages of peptidoglycan synthesis, transglycosylation and transpeptidation in particular. Although there are multiple types of PBPs, they all bind penicillin (however, with different affinities) and this is what is important for this article.

As the bacteria infiltrates the organism, it becomes necessary to somehow destroy it. One way is to to break this cell wall. To achieve this, the penicillin is introduced to the bacteria that later reacts with PBPs (using β-lactam ring ), preventing it from catalyzing the formation of a peptidoglycan and, as a result, stops the formation of a cell wall. However, many pathogenic bacteria have evolved a way to mutate themselves to be immune to various drugs that contain this β-lactam rings. What happens is that bacterium produces enzyme, called β-lactamase that cleaves the β-lactam ring on a penicillin and thus preventing it from reacting with PBPs. To solve this problem, the new drug, called, lactivicin was developed that contains gamma-lactone rings and cycloserine as substitutions to β-lactam. So far, it has proved to be an efficient antibiotic. It successfully binds to PBPs and prevents cell wall from forming. Recently, an analog of lactivicin, phenoxylactivicin (PLTV) was developed and is discussed in this article.

The complex of the PBP with phenoxylactivicin is shown on the picture.

Picture on the right is displayed as N-terminus to C-termiunus Rainbow for PBP complex . The coloring goes as shown on the sample:

Amino Terminus

Carboxy Terminus

Overall Structure

Penicillin Binding Proteins have specific structures and designs that promote allow the binding of Penicillin and other antibiotics. One of the enzymes within the PBP family is D-alanyl-D-alanine carboxypeptidase/transpeptidase. This enzyme is responsible for the link between two chains in the peptidoglycan network [1]. DA-DA peptidase’s structure contains a serine in the active site. Ser 62 is used to bind a peptide strand which would then link to another strand of the network, and this is the site where penicillin binds and inhibits the protein. This enzyme is split into two sections, which will be referred to as the North and South regions. The North Region contains both the carboxyl and amino termini, two α-helices, and a nine-stranded antiparallel β-sheet [2]. This leads the Northern region of the enzyme to appear symmetrical. Both termini lead are connected to helices and then into β-strands. Inbetween the sets of strands the South region of the peptide is formed and this is strictly made out of helices. In the center of the two regions is where the Ser 62 active site resides, and this is also at the symmetrical center of the protein. The protein essentially forms a cupped hand, with the center of the palm being the active site, the bottom of the palm being a series of 8 or so helices, the knuckles being the β-strands, and the tips of the fingers being the two helices of the North region.

Binding Interactions

Penicillin binding protein binds to beta-lactam antibiotics because they are similar in chemical structure to the modular pieces that form the peptioglycan . The beta-lactam amide bond is ruptured to form a covalent bond with the catalytic serine at the binding protein's active site.

Additional Features

1)role in antibiotics and resistance the role of PBPsmetabolic pathways and enzymes are unique to bacteria in its synthesis is a very good target for drugs of selective toxicity

2)different PBPs and how they are classified into diverse categories found as both membrane-bound and cytoplasmic proteins

3)work as enzyme to catalyze synthesis of peptidoglycan

Quiz Question 1

Question related to PBP evolution and developing resistance to ß-lactams, likely related to active site mutations. Shows the conserved residues of Penicillin Binding Protein from most conserved to most variable.

See Also

• Penicillin-binding protein
• 2y2g
• 2bg1
• 2fff
• 2jch

Credits

Introduction - Anton El Khoury

Overall Structure - Tyler Carpenter

Drug Binding Site - Hyunjoon Choi

Additional Features - Tiankai Zhang

Quiz Question 1 - Samuel Pierce

References

1. Goodsell, David. "Penicillin-binding Proteins." Penicillin-binding Proteins. May 2002. Web. 07 Apr. 2016. 2. Kelly, J. A., and A. P. Kuzin. "3PTE." RCSB PDB. Web. 07 Apr. 2016.