5j5d: Difference between revisions
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<StructureSection load='5j5d' size='340' side='right' caption='[[5j5d]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5j5d' size='340' side='right' caption='[[5j5d]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5j5d]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J5D FirstGlance]. <br> | <table><tr><td colspan='2'>[[5j5d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Myctu Myctu]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J5D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J5D FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GT:2-OXOHEPTANEDIOIC+ACID'>6GT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6GT:2-OXOHEPTANEDIOIC+ACID'>6GT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dapA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=83332 MYCTU])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/4-hydroxy-tetrahydrodipicolinate_synthase 4-hydroxy-tetrahydrodipicolinate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.3.3.7 4.3.3.7] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/4-hydroxy-tetrahydrodipicolinate_synthase 4-hydroxy-tetrahydrodipicolinate synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.3.3.7 4.3.3.7] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5d OCA], [http://pdbe.org/5j5d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j5d RCSB], [http://www.ebi.ac.uk/pdbsum/5j5d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5d ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5j5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5d OCA], [http://pdbe.org/5j5d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j5d RCSB], [http://www.ebi.ac.uk/pdbsum/5j5d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5d ProSAT]</span></td></tr> | ||
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== Function == | == Function == | ||
[[http://www.uniprot.org/uniprot/DAPA_MYCTU DAPA_MYCTU]] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).<ref>PMID:18062777</ref> | [[http://www.uniprot.org/uniprot/DAPA_MYCTU DAPA_MYCTU]] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).<ref>PMID:18062777</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L-aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB). Alpha-ketopimelic acid (alpha-KPA) showed maximum inhibition of 88% and IC50 of 21 muM in the presence of pyruvate (500 muM) and ASA (400 muM). Competition experiments with pyruvate and ASA revealed competition of alpha-KPA with pyruvate. Liquid chromatography-mass spectrometry (LC-MS) data with multiple reaction monitoring (MRM) showed that the relative abundance peak of final product, 2,3,4,5-tetrahydrodipicolinate, was decreased by 50%. Thermal shift assays showed 1 degrees C Tm shift of Mtb-rDapA upon binding alpha-KPA. The 2.4 A crystal structure of Mtb-rDapA-alpha-KPA complex showed the interaction of critical residues at the active site with alpha-KPA. Molecular dynamics simulations over 500 ns of pyruvate docked to Mtb-DapA and of alpha-KPA-bound Mtb-rDapA revealed formation of hydrogen bonds with pyruvate throughout in contrast to alpha-KPA. Molecular descriptors analysis showed that ligands with polar surface area of 91.7 A(2) are likely inhibitors. In summary, alpha-hydroxypimelic acid and other analogues could be explored further as inhibitors of Mtb-DapA. | |||
Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues.,Shrivastava P, Navratna V, Silla Y, Dewangan RP, Pramanik A, Chaudhary S, Rayasam G, Kumar A, Gopal B, Ramachandran S Sci Rep. 2016 Aug 9;6:30827. doi: 10.1038/srep30827. PMID:27501775<ref>PMID:27501775</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5j5d" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: 4-hydroxy-tetrahydrodipicolinate synthase]] | [[Category: 4-hydroxy-tetrahydrodipicolinate synthase]] | ||
[[Category: Myctu]] | |||
[[Category: Gopal, B]] | [[Category: Gopal, B]] | ||
[[Category: Navratna, V]] | [[Category: Navratna, V]] | ||
Revision as of 09:36, 20 December 2017
Crystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acidCrystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acid
Structural highlights
Function[DAPA_MYCTU] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (Probable).[1] Publication Abstract from PubMedThe Mycobacterium tuberculosis dihydrodipicolinate synthase (Mtb-dapA) is an essential gene. Mtb-DapA catalyzes the aldol condensation between pyruvate and L-aspartate-beta-semialdehyde (ASA) to yield dihydrodipicolinate. In this work we tested the inhibitory effects of structural analogues of pyruvate on recombinant Mtb-DapA (Mtb-rDapA) using a coupled assay with recombinant dihydrodipicolinate reductase (Mtb-rDapB). Alpha-ketopimelic acid (alpha-KPA) showed maximum inhibition of 88% and IC50 of 21 muM in the presence of pyruvate (500 muM) and ASA (400 muM). Competition experiments with pyruvate and ASA revealed competition of alpha-KPA with pyruvate. Liquid chromatography-mass spectrometry (LC-MS) data with multiple reaction monitoring (MRM) showed that the relative abundance peak of final product, 2,3,4,5-tetrahydrodipicolinate, was decreased by 50%. Thermal shift assays showed 1 degrees C Tm shift of Mtb-rDapA upon binding alpha-KPA. The 2.4 A crystal structure of Mtb-rDapA-alpha-KPA complex showed the interaction of critical residues at the active site with alpha-KPA. Molecular dynamics simulations over 500 ns of pyruvate docked to Mtb-DapA and of alpha-KPA-bound Mtb-rDapA revealed formation of hydrogen bonds with pyruvate throughout in contrast to alpha-KPA. Molecular descriptors analysis showed that ligands with polar surface area of 91.7 A(2) are likely inhibitors. In summary, alpha-hydroxypimelic acid and other analogues could be explored further as inhibitors of Mtb-DapA. Inhibition of Mycobacterium tuberculosis dihydrodipicolinate synthase by alpha-ketopimelic acid and its other structural analogues.,Shrivastava P, Navratna V, Silla Y, Dewangan RP, Pramanik A, Chaudhary S, Rayasam G, Kumar A, Gopal B, Ramachandran S Sci Rep. 2016 Aug 9;6:30827. doi: 10.1038/srep30827. PMID:27501775[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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