Sandbox Reserved 1068: Difference between revisions
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Inhibition studies have also shown a switch in binding mode at the MbtI active site for inhibitors carrying a substituted enolpyruvyl group compared to the chorismate substrate <ref name="5a">PMID:22607697</ref> <ref name= | Inhibition studies have also shown a switch in binding mode at the MbtI active site for inhibitors carrying a substituted enolpyruvyl group compared to the chorismate substrate <ref name="5a">PMID:22607697</ref> <ref name= | ||
"2a">PMID:23108268</ref> <ref name="1a">PMID:20512795</ref>. Crystal structures and fluorescent-based thermal shift assays show that substituents larger than a methyl group are accommodated in the active site of MbtI through localized flexibility in the peptide backbone.<ref name="5a"/> Positioning of the <scene name='69/694235/3st6_structure_bindingpocket/3'>active site residues</scene> of MbtI in [[3ST6]] with the inhibitor AMT bound is highly similar to the positioning of the <scene name='69/694235/3log_bindingpocket/3'>active site residues</scene> in closed form of MbtI [[3log]] with succinic acid bound <ref name= "5a"/>. The AMT inhibitor contains an unmodified enolpyruvyl side chain and resembles the structure of the natural substrate, chorismate. [[3log]] and [[3ST6]] are shown to share a similar binding mode, termed binding mode 1. Isochorismate inhibitors with modified enolpyruvl side chains ([[3VEH]], [[3RV9]], [[3RV8]], [[3RV7]], [[3RV6]]) utilize a novel binding mode, termed mode 2, which involves the <scene name='69/694235/3veh_structure_bindingpocket2/2'>reorientation of the isochorismate analogue within the active site</scene>. Movement of the peptide backbone away from the closed form of MbtI is required to accommodate the enolpyruyl modified inhibitors. | "2a">PMID:23108268</ref> <ref name="1a">PMID:20512795</ref>. Crystal structures and fluorescent-based thermal shift assays show that substituents larger than a methyl group are accommodated in the active site of MbtI through localized flexibility in the peptide backbone.<ref name="5a"/> Positioning of the <scene name='69/694235/3st6_structure_bindingpocket/3'>active site residues</scene> of MbtI in [[3ST6]] with the inhibitor AMT bound is highly similar to the positioning of the <scene name='69/694235/3log_bindingpocket/3'>active site residues</scene> in closed form of MbtI [[3log]] with succinic acid bound <ref name= "5a"/>. The AMT inhibitor contains an unmodified enolpyruvyl side chain and resembles the structure of the natural substrate, chorismate. [[3log]] and [[3ST6]] are shown to share a similar binding mode, termed binding mode 1. Isochorismate inhibitors with modified enolpyruvl side chains ([[3VEH]], [[3RV9]], [[3RV8]], [[3RV7]], [[3RV6]]) utilize a novel binding mode, termed mode 2, which involves the <scene name='69/694235/3veh_structure_bindingpocket2/2'>reorientation of the isochorismate analogue within the active site</scene>. Movement of the peptide backbone away from the closed form of MbtI is required to accommodate the enolpyruyl modified inhibitors. | ||
[[Image:Screen Shot 2015-04-26 at 6.29.56 PM.png|300 px|center|thumb|Figure 3: Isochorismate pyruvate activity <ref name= "8a"/>.]] | |||
==Molecular Mechanism== | ==Molecular Mechanism== | ||
