Sandbox Reserved 1499
From Proteopedia
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== Structure== | == Structure== | ||
<StructureSection load='3ita' size='340' side='right' caption='PBP6, [[Resolution|resolution]] 1.80Å' scene='80/802673/Default/1'> | <StructureSection load='3ita' size='340' side='right' caption='PBP6, [[Resolution|resolution]] 1.80Å' scene='80/802673/Default/1'> | ||
| - | PBP6 is a monomeric enzyme with an active site near its N-terminal domain. | + | PBP6 is a monomeric enzyme with a C-terminal domain rich in beta-sheets and an active site localised near its N-terminal domain<ref>PMID:22126997</ref>. |
===Active site=== | ===Active site=== | ||
The amino acids that compose the <scene name='80/802673/Active_site_1/1'>active site</scene> are: Ser40 and Lys43, which are organised in a catalytic diad through a hydrogen bond, alongside with Ser106, Asp108, Lys209 and Thr210. | The amino acids that compose the <scene name='80/802673/Active_site_1/1'>active site</scene> are: Ser40 and Lys43, which are organised in a catalytic diad through a hydrogen bond, alongside with Ser106, Asp108, Lys209 and Thr210. | ||
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Other amino acids allow the selective fixation of the ligand to the enzyme. The residues 79 to 83, 212 to 218 and 242 to 248 are responsible for this. These residues undergo a conformation change during substrate fixation which changes the configuration of the entire enzyme and gives the substrate access to the active site. | Other amino acids allow the selective fixation of the ligand to the enzyme. The residues 79 to 83, 212 to 218 and 242 to 248 are responsible for this. These residues undergo a conformation change during substrate fixation which changes the configuration of the entire enzyme and gives the substrate access to the active site. | ||
| - | + | Ser83, specifically, is thought to be capable of stabilising the leaving group during the acylation reaction through hydrogen bonds. | |
Another important part of the selective fixation process is the oxyanion hole, which is a hole in the enzyme structure created by the backbone nitrogens of Ser40 and Thr212. These nitrogens can interact with the carbonyl oxygen from the D-Ala-D-Ala peptide bond, thus stabilising it. | Another important part of the selective fixation process is the oxyanion hole, which is a hole in the enzyme structure created by the backbone nitrogens of Ser40 and Thr212. These nitrogens can interact with the carbonyl oxygen from the D-Ala-D-Ala peptide bond, thus stabilising it. | ||
Current revision
| This Sandbox is Reserved from 06/12/2018, through 30/06/2019 for use in the course "Structural Biology" taught by Bruno Kieffer at the University of Strasbourg, ESBS. This reservation includes Sandbox Reserved 1480 through Sandbox Reserved 1543. |
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Penicillin-binding protein 6 from Escherichia coli
The Penicillin-binding protein 6 (PBP6) from Escherichia coli is a DD-carboxypeptidase which plays an important role in the creation of the bacterial cell wall. It belongs to the group of PBP of low molecular mass. Its structure was determined by Chen et al.[1]. These results allow for the study of the functioning of the active site of PBP6 and of the role of pentapeptidic imitation by ampicillin.
Contents |
Function
As a DD-carboxypeptidase, the function of PBP6 is to participate in the transpeptidation which occurs during the biosynthesis of peptidoglycan [2]. More specifically, it cleaves the peptide bond between the two terminal D-alanines of the pentapeptidic muramyl peptides of sequence L-Ala-D-Glu-m-A2pm-D-Ala-D-Ala. This then allows transpeptidases to create peptidoglycan cross-links which stabilise the cell wall.
The cleavage reaction takes place in two steps.
- Firstly, the PBP6 binds to carbonyl group in the peptide bond between the two C-terminal D-alanines of the N-acetylmuramic acid[3]. This forms a high-energy tetrahedric intermediate called the acylenzyme.
- The acylenzyme allows the medium to reach the carbonyle group. As a result, a water molecule can attack the group, causing the cleavage of the tetrahedral structure.
Structure
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Relevance
The resolution of this structure plays an important role in understanding the exact method of action of beta-lactam antibiotics[5]. Since antibiotic resistance is often based on small changes in protein conformation at the molecular level, it is important to understand the method of action of antibiotics in their every detail, so that treatments for resistant bacteria can be devised.
References
- ↑ Chen Y, Zhang W, Shi Q, Hesek D, Lee M, Mobashery S, Shoichet BK. Crystal structures of penicillin-binding protein 6 from Escherichia coli. J Am Chem Soc. 2009 Oct 14;131(40):14345-54. PMID:19807181 doi:10.1021/ja903773f
- ↑ Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008 Mar;32(2):234-58. doi: 10.1111/j.1574-6976.2008.00105.x., Epub 2008 Feb 11. PMID:18266856 doi:http://dx.doi.org/10.1111/j.1574-6976.2008.00105.x
- ↑ Mattei PJ, Neves D, Dessen A. Bridging cell wall biosynthesis and bacterial morphogenesis. Curr Opin Struct Biol. 2010 Dec;20(6):749-55. doi: 10.1016/j.sbi.2010.09.014., Epub 2010 Oct 26. PMID:21030247 doi:http://dx.doi.org/10.1016/j.sbi.2010.09.014
- ↑ van Heijenoort J. Peptidoglycan hydrolases of Escherichia coli. Microbiol Mol Biol Rev. 2011 Dec;75(4):636-63. doi: 10.1128/MMBR.00022-11. PMID:22126997 doi:http://dx.doi.org/10.1128/MMBR.00022-11
- ↑ Llarrull LI, Testero SA, Fisher JF, Mobashery S. The future of the beta-lactams. Curr Opin Microbiol. 2010 Oct;13(5):551-7. doi: 10.1016/j.mib.2010.09.008. Epub, 2010 Sep 29. PMID:20888287 doi:http://dx.doi.org/10.1016/j.mib.2010.09.008
