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Introduction

MraY, called also phospho-N-acetylmuramoyl-pentapeptide-transferase or UDP-MurNAc-pentapeptide phosphotransferase, with EC number 2.7.8.13, is an integral membrane enzyme involved in peptidoglycan biosynthesis ^{[1] [2]}.MraY is encoded by the mraY gene and belongs to a subfamily of the polyprenyl-phosphate N-acetyl hexosamine 1-phosphate transferase (PNPT) superfamily ^[3]. MRAY is a promising candidate for the development of new antibiotics. In fact, it is the target of five classes of natural nucleoside inhibitors with potent antibacterial activity ^{[2] [4]}.

The structure presented in this page correspond to the MraY protein from Aquifex aeolicus (strain VF5), expressed in Escherichia coli, in complex with carbacaprazamycin.

carbacaprazamycin ( je vais ajouter en peu d'info sur carbacaprazamycin...)

Function

MraY is a critical enzyme in peptidoglycan biosynthesis. Peptidoglycan is an essential component of the cell wall of Gramnegative and Gram-positive bacteria ^[5]. The cell wall provides bacteria a structural support and protection. In particular, it allows bacteria to maintain their cell shape at different osmotic pressures ^[6]. Peptidoglycan is a cross-linked polymer of carbohydrates an amino acids and due to its biological relevance in Bacteria, it has been a major target for antibiotics ^{[3] [5]}.

Peptidoglycan biosynthesis involves three main stages. MraY is responsible for the second stage. First, the peptidoglycan precursor UDP-Nacetylmuramoyl (MurNAc)–pentapeptide is synthesized in the cytosol. Second, this hydrophilic precursor is attached to a lipid carrier, and the complex lipid carrier-precursor is transported, through the membrane, to the periplasm. Third, the peptidoglycan precursors are polymerized to form the cell wall. MraY catalyzes the transfer of phospho-MurNAc-pentapeptide from hydrophilic substrate UDP-MurNAc-pentapeptide to the lipid carier (C55-P) in the presence of a Mg2+ cofactor. The product is the undecaprenyl-pyrophosphoryl-MurNAcpentapeptide, also known as lipid I ^{[3] [7] [8]}.

Structure

MraY is a membrane-bound enzyme, for which the N and the C termini are located on the periplasmic side. This protein is made of four extracellular loops, five cytoplasmic loops (named A,B … and E) and ten transmembrane helices named TM1 to TM10. Though, TM9 is cleaved by a glycin residue into two helical segments named TM9a and TM9b. Furthermore, there is an additional helix between TM9b and TM10, which is only 11 residues long and is called TM9c. This helix contains a HHH motif (H290, 291 and 292) which plays a role in the enzyme’s substrat selectivity and is a part of the catalytic site [1]. For example; they interact with tunicamycin and MD2. This small loop binds two Ni2+ ions, one on the two first histidines and the other one on the last one. Another part of this site is the residues corresponding to Asp117 and Asp118 which are involved in Mg2+coordination [4].TM5–TM10 and loops C and D also play a role in the catalytic site and contain many polar and charged amino acids residues[1]. Also, some polar and charged amino acids on TM9b and loop E are pointing toward the active site, making it even more hydrophilic [4].

3D related structures

• 4j72:Crystal Structure of polyprenyl-phosphate N-acetyl hexosamine 1-phosphate transferase (MraY)
• 6oyz:Crystal structure of MraY bound to capuramycin
• 5ckr:Crystal Structure of MraY in complex with Muraymycin D2
• 6oz6:Crystal structure of MraY bound to 3'-hydroxymureidomycin A
• 5jnq:MraY tunicamycin complex

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