Sandbox 124
From Proteopedia
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<Structure load='4dki' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | <Structure load='4dki' size='500' frame='true' align='right' caption='Insert caption here' scene='Insert optional scene name here' /> | ||
| - | '''Introduction''' | + | ==='''Introduction'''=== |
| - | <scene name='37/372724/ | + | <scene name='37/372724/Tp_1_in_grey/1'>Transpeptidase</scene>(TP), also known as penicillin-binding proteins (PBP), |
catalyze the cross-linking of peptidoglycan polymers during bacterial cell wall | catalyze the cross-linking of peptidoglycan polymers during bacterial cell wall | ||
synthesis. The natural transpeptidase substrate is the D-Ala-D-Ala | synthesis. The natural transpeptidase substrate is the D-Ala-D-Ala | ||
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inhibit transpeptidases by mimicking the D-Ala-D-Ala substrate, resulting in | inhibit transpeptidases by mimicking the D-Ala-D-Ala substrate, resulting in | ||
the inhibition of cell wall synthesis and ultimately bacterial cell growth. | the inhibition of cell wall synthesis and ultimately bacterial cell growth. | ||
| - | Overuse and misuse of β-lactams has led to the generation of | + | Overuse and misuse of β-lactams has led to the generation of methicillin resistant |
Staphylococcus aureus (MRSA) isolates that have acquired an | Staphylococcus aureus (MRSA) isolates that have acquired an | ||
alternative transpeptidase, PBP2a, which is neither bound nor inhibited by β- | alternative transpeptidase, PBP2a, which is neither bound nor inhibited by β- | ||
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using 3D printing technology to illustrate the mechanism of action of | using 3D printing technology to illustrate the mechanism of action of | ||
ceftobiprole. Supported by a grant from the Camille and Henry Dreyfus Foundation.''' | ceftobiprole. Supported by a grant from the Camille and Henry Dreyfus Foundation.''' | ||
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| + | ==='''How does PBP2a works?'''=== | ||
| + | PBP2a is composed of two domains: a <scene name='37/372724/Non_penicillin_binding/1'>non penicillin binding</scene> (NPB) domain and a | ||
| + | <scene name='37/372724/Transpeptidase_domain/1'>TP</scene> domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain “sits” in the periplasm with its active site facing the inner surface of the cell wall. The active site contains a serine residue at position 403 (Ser403) which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | ||
Revision as of 18:35, 24 July 2013
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Introduction
(TP), also known as penicillin-binding proteins (PBP), catalyze the cross-linking of peptidoglycan polymers during bacterial cell wall synthesis. The natural transpeptidase substrate is the D-Ala-D-Ala peptidoglycan side chain terminus. Beta-lactam (β-lactam) antibiotics, which include penicillins, cephalosporins and carbapenems, bind and irreversibly inhibit transpeptidases by mimicking the D-Ala-D-Ala substrate, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of β-lactams has led to the generation of methicillin resistant Staphylococcus aureus (MRSA) isolates that have acquired an alternative transpeptidase, PBP2a, which is neither bound nor inhibited by β- lactams. MRSA isolates are resistant to all β-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Furthermore, they are often only susceptible to “last resort antibiotics”, such as vancomycin. Recently, two cephalosporins - ceftobiprole and ceftaroline - that bind and inhibit PBP2a have been developed. The Hostos-Lincoln Academy Students Modeling A Research Topic (SMART) Team generated a model of the PBP2a/ceftobiprole complex (PDB 4DKI) using 3D printing technology to illustrate the mechanism of action of ceftobiprole. Supported by a grant from the Camille and Henry Dreyfus Foundation.
How does PBP2a works?
PBP2a is composed of two domains: a (NPB) domain and a domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain “sits” in the periplasm with its active site facing the inner surface of the cell wall. The active site contains a serine residue at position 403 (Ser403) which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links.
