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==Crystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acid== | ==Crystal structure of Dihydrodipicolinate Synthase from Mycobacterium tuberculosis in complex with alpha-ketopimelic acid== | ||
<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 [ | <table><tr><td colspan='2'>[[5j5d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. 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 [https://proteopedia.org/fgij/fg.htm?mol=5J5D FirstGlance]. <br> | ||
</td></tr><tr id=' | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> | ||
<tr id=' | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6GT:2-OXOHEPTANEDIOIC+ACID'>6GT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5j5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j5d OCA], [https://pdbe.org/5j5d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5j5d RCSB], [https://www.ebi.ac.uk/pdbsum/5j5d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5j5d ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://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> | |||
==See Also== | |||
*[[Dihydrodipicolinate synthase|Dihydrodipicolinate synthase]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Mycobacterium tuberculosis H37Rv]] | ||
[[Category: | [[Category: Gopal B]] | ||
[[Category: | [[Category: Navratna V]] | ||