Sandbox Reserved 1061: Difference between revisions
From Proteopedia
Jump to navigationJump to search
No edit summary |
No edit summary |
||
| Line 7: | Line 7: | ||
== Background == | == Background == | ||
''Mycobacterium tuberculosis'' [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Wikipedia]resides in the lungs of a host and upon becoming active, results in symptoms such as chest pains, weakness, and intense coughing. Left untreated and unmanaged, TB can lead to death (1.5 million in 2013).<ref>"Tuberculosis." Media Centre. World Health Organization, Web. 16 Mar. 2015. Media Centre. <http://www.who.int/mediacentre/factsheets/fs104/en/>.</ref>The disease has a high co-morbidity with HIV/AIDS due to its immunocompromising tendencies. Tuberculosis is one of the most heavily studied diseases today. With over 9 million infections worldwide per year, the necessity for antimicrobial agents to combat emerging multi-drug resistant strands is imperative. | ''Mycobacterium tuberculosis'' [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Wikipedia]resides in the lungs of a host and upon becoming active, results in symptoms such as chest pains, weakness, and intense coughing. Left untreated and unmanaged, TB can lead to death (1.5 million in 2013).<ref>"Tuberculosis." Media Centre. World Health Organization, Web. 16 Mar. 2015. Media Centre. <http://www.who.int/mediacentre/factsheets/fs104/en/>.</ref>The disease has a high co-morbidity with HIV/AIDS due to its immunocompromising tendencies. Tuberculosis is one of the most heavily studied diseases today. With over 9 million infections worldwide per year, the necessity for antimicrobial agents to combat emerging multi-drug resistant strands is imperative. <ref>"Tuberculosis." Media Centre. World Health Organization, Web. 16 Mar. 2015. Media Centre. <http://www.who.int/mediacentre/factsheets/fs104/en/>.</ref> | ||
| Line 13: | Line 13: | ||
== Structure == | == Structure == | ||
The structure of ''M. tuberculosis'' as determined by x-ray crystallography has 79 residues in a single polypeptide chain. <scene name='69/694228/Nrdh_structure/1'>NrdH Chrystal Structure</scene>. The active site (shown in green) is dominated by a | The structure of ''M. tuberculosis'' as determined by x-ray crystallography has 79 residues in a single polypeptide chain. <scene name='69/694228/Nrdh_structure/1'>NrdH Chrystal Structure</scene>. The active site (shown in green) is dominated by a disulfide bond between Cys-11 and Cys-14, which serves as the site of reduction by theirodoxin reductase. <ref>Swastik, Phulera and Mande, Shekhar C. (2013) The Crystal Structure of Mycobacterium tuberculosis NrdH at 0.87Å Suggests a Possible Mode of Its Activity. Biochemistry 52, 4056-4065.</ref> | ||
Many theirodoxin-like proteins have a similar active site region, denoted as the theirodoxin fold, which occurs directly before the disulfide bond. The residues in this region, denoted by letters CVQC, are the most highly conserved of all areas of the protein across multiple species. Exactly how this structure relates to function is somewhat debated. A | Many theirodoxin-like proteins have a similar active site region, denoted as the theirodoxin fold, which occurs directly before the disulfide bond. The residues in this region, denoted by letters CVQC, are the most highly conserved of all areas of the protein across multiple species. Exactly how this structure relates to function is somewhat debated. A threonine-7 reside directly across the theirodoxin fold from the disulfide bond has been suggested to adopt two different conformations which differentially affect the redox abilities of the protein. In the <scene name='69/694228/Nrdh_ligand_binding_site/8'>"A" Conformation</scene>, the alcohol of the threonine side chain points towards the disulfide bond, engaging an ionic interaction between the two that prevents therodoxin reductase from binding. Alternatively, in the <scene name='69/694228/Nrdh_ligand_binding_site/12'>"B" Conformation</scene>, the alcohol points in the opposite direction, allowing sufficient space for the ligand to bind and reduction to occur.<ref>Swastik, Phulera and Mande, Shekhar C. (2013) The Crystal Structure of Mycobacterium tuberculosis NrdH at 0.87Å Suggests a Possible Mode of Its Activity. Biochemistry 52, 4056-4065.</ref> | ||
The active site of the protein is stabilized through a <scene name='69/696879/Water_coordination/1'>hydrogen bond network</scene> involving the two highly conserved residues, CVQC and [http://www.proteopedia.org/wiki/index.php/Image:Weblogowsgfrp.png WSGFRP]. The crystal structure shows that interactions with one water molecule is necessary for the proper coordination between the conserved motifs to occur. These hydrogen bonds orient the important residues in the most optimal position to promote oxidation and reduction.<ref>Swastik, Phulera and Mande, Shekhar C. (2013) The Crystal Structure of Mycobacterium tuberculosis NrdH at 0.87Å Suggests a Possible Mode of Its Activity. Biochemistry 52, 4056-4065.</ref> | The active site of the protein is stabilized through a <scene name='69/696879/Water_coordination/1'>hydrogen bond network</scene> involving the two highly conserved residues, CVQC and [http://www.proteopedia.org/wiki/index.php/Image:Weblogowsgfrp.png WSGFRP]. The crystal structure shows that interactions with one water molecule is necessary for the proper coordination between the conserved motifs to occur. These hydrogen bonds orient the important residues in the most optimal position to promote oxidation and reduction.<ref>Swastik, Phulera and Mande, Shekhar C. (2013) The Crystal Structure of Mycobacterium tuberculosis NrdH at 0.87Å Suggests a Possible Mode of Its Activity. Biochemistry 52, 4056-4065.</ref> | ||
