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Protein Sci ; 33(6): e5002, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38723146

RESUMEN

Bacteria that have acquired resistance to most antibiotics, particularly those causing nosocomial infections, create serious problems. Among these, the emergence of vancomycin-resistant enterococci was a tremendous shock, considering that vancomycin is the last resort for controlling methicillin-resistant Staphylococcus aureus. Therefore, there is an urgent need to develop an inhibitor of VanX, a protein involved in vancomycin resistance. Although the crystal structure of VanX has been resolved, its asymmetric unit contains six molecules aligned in a row. We have developed a structural model of VanX as a stable dimer in solution, primarily utilizing nuclear magnetic resonance (NMR) residual dipolar coupling. Despite the 46 kDa molecular mass of the dimer, the analyses, which are typically not as straightforward as those of small proteins around 10 kDa, were successfully conducted. We assigned the main chain using an amino acid-selective unlabeling method. Because we found that the zinc ion-coordinating active sites in the dimer structure were situated in the opposite direction to the dimer interface, we generated an active monomer by replacing an amino acid at the dimer interface. The monomer consists of only 202 amino acids and is expected to be used in future studies to screen and improve inhibitors using NMR.


Asunto(s)
Proteínas Bacterianas , Multimerización de Proteína , D-Ala-D-Ala Carboxipeptidasa de Tipo Serina , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Dominio Catalítico , Metaloendopeptidasas/química , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , D-Ala-D-Ala Carboxipeptidasa de Tipo Serina/química , D-Ala-D-Ala Carboxipeptidasa de Tipo Serina/metabolismo , D-Ala-D-Ala Carboxipeptidasa de Tipo Serina/fisiología , Resistencia a la Vancomicina/genética , Staphylococcus aureus Resistente a Meticilina/enzimología , Staphylococcus aureus Resistente a Meticilina/metabolismo
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