Proteins from Mycobacterium tuberculosis: Difference between revisions

The ''B. subtilis'' AcpS trimer ([[1f80]]) <scene name='3hqj/Acp/2'>binds</scene> three molecules of the acyl carrier protein (ASP). The interactions between ''B. subtilis'' AcpS and ACP are predominantly <scene name='3hqj/Acp/3'>electrostatic</scene>. The ''B. subtilis'' AcpS (white) is shown in spacefill representation, the agrinines, lysines, and histidines are colored <font color='blue'><b>blue</b></font>, while aspartates and glutamates are colored <font color='red'><b>red</b></font>. The ACP molecule (<span style="color:lime;background-color:black;font-weight:bold;">green</span>) is shown in ribbon representation with aspartates and glutamates as sticks and colored <font color='red'><b>red</b></font>. The ''B. subtilis'' AcpS has large <scene name='3hqj/Acp/4'>electropositive interface</scene> with ASP. <scene name='3hqj/Acp/5'>Electrostatic representation</scene> of ''Mtb'' AcpS surface using the similar orientation as ''B. subtilis'' AcpS, shows a moderate electronegative nature in the putative ACP binding site near the <font color='red'><b>ASP 15</b></font>. The ''Mtb'' ASPM structure ([[1klp]], corresponding to ACP) demonstrates considerably lower negative charge. So, the electrostatic interactions between ''Mtb'' AcpS and ASPM are, probably, less important.

Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to pyrazinamide represents an important public health problem, as both first- and second-line treatment regimens include pyrazinamide. It becomes toxic to ''Mycobacterium tuberculosis'' when converted to pyrazinoic acid by the <scene name='Journal:JBSD:11/Cv/5'>bacterial pyrazinamidase (PncA) enzyme</scene>. PZA resistance is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are resistance for <scene name='Journal:JBSD:11/Cv/6'>PZA</scene>. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three dimensional conformational behaviour of <scene name='Journal:JBSD:11/Cv/3'>native</scene> and mutants PncA. Our analysis clearly indicates that the mutation (<scene name='Journal:JBSD:11/Cv/8'>D8G</scene>, <scene name='Journal:JBSD:11/Cv/9'>S104R</scene> and <scene name='Journal:JBSD:11/Cv/10'>C138Y</scene>) in PncA is responsible for rigid binding cavity which in turns abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighboring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding-site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps there researchers to design new inhibitor with consideration of rigid criterion of binding residues due to mutation of this essential target.

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