Sandbox Reserved 429

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='Saves cells from dying since the appearance of life (2jch)' scene='48/483886/Rainbow/1'>

Introduction

Outline: 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). The goal of a chemist is to develop a way to break this cell wall, thus destroying the bacteria. To achieve this, the penicillin is introduced to the bacteria and then reacts with PBPs (using β-lactam ring), preventing it from forming 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 left is displayed as N-terminus to C-termiunus Rainbow for PBP complex. The coloring goes as shown on the sample:

Amino Terminus

Carboxy Terminus

2) Ligands, in particular phenoxyacetyl lactivicin. Also, how PBP binds lactivicin. Sample green scene: Penicillin-binding protein has four ligands, one of which is the electron-deficient olefin ligand or EDO

Overall Structure

The secondary structures of PBP have certain affects on ligands TextToBeDisplayed Ligand has oxyanion hole to further binding potential. How does this help?

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