3hij: Difference between revisions
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< | ==Crystal structure of dihydrodipicolinate synthase from Bacillus anthracis in complex with its substrate, pyruvate== | ||
<StructureSection load='3hij' size='340' side='right'caption='[[3hij]], [[Resolution|resolution]] 2.15Å' scene=''> | |||
You may | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3hij]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/"bacillus_cereus_var._anthracis"_(cohn_1872)_smith_et_al._1946 "bacillus cereus var. anthracis" (cohn 1872) smith et al. 1946]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3HIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3HIJ FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | |||
- | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KPI:(2S)-2-AMINO-6-[(1-HYDROXY-1-OXO-PROPAN-2-YLIDENE)AMINO]HEXANOIC+ACID'>KPI</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1xl9|1xl9]], [[1xky|1xky]]</div></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">dapA-2, dapA2, BAS3650, BA_3935, GBAA3935, GBAA_3935 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1392 "Bacillus cereus var. anthracis" (Cohn 1872) Smith et al. 1946])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3hij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3hij OCA], [https://pdbe.org/3hij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3hij RCSB], [https://www.ebi.ac.uk/pdbsum/3hij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3hij ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[https://www.uniprot.org/uniprot/Q81WN7_BACAN Q81WN7_BACAN]] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (By similarity).[SAAS:SAAS020625_004_011311][HAMAP-Rule:MF_00418] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/hi/3hij_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3hij ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Bacillus anthracis is a gram-positive spore-forming bacterium that causes anthrax. With the increased threat of anthrax in biowarfare, there is an urgent need to characterize new antimicrobial targets from B. anthracis. One such target is dihydrodipicolinate synthase (DHDPS), which catalyzes the committed step in the pathway yielding meso-diaminopimelate and lysine. In this study, we employed CD spectroscopy to demonstrate that the thermostability of DHDPS from B. anthracis (Ba-DHDPS) is significantly enhanced in the presence of the substrate, pyruvate. Analytical ultracentrifugation studies show that the tetramer-dimer dissociation constant of the enzyme is 3-fold tighter in the presence of pyruvate compared with the apo form. To examine the significance of this substrate-mediated stabilization phenomenon, a dimeric mutant of Ba-DHDPS (L170E/G191E) was generated and shown to have markedly reduced activity compared with the wild-type tetramer. This demonstrates that the substrate, pyruvate, stabilizes the active form of the enzyme. We next determined the high resolution (2.15 A) crystal structure of Ba-DHDPS in complex with pyruvate (3HIJ) and compared this to the apo structure (1XL9). Structural analyses show that there is a significant (91 A(2)) increase in buried surface area at the tetramerization interface of the pyruvate-bound structure. This study describes a new mechanism for stabilization of the active oligomeric form of an antibiotic target from B. anthracis and reveals an "Achilles heel" that can be exploited in structure-based drug design. | |||
Substrate-mediated stabilization of a tetrameric drug target reveals Achilles heel in anthrax.,Voss JE, Scally SW, Taylor NL, Atkinson SC, Griffin MD, Hutton CA, Parker MW, Alderton MR, Gerrard JA, Dobson RC, Dogovski C, Perugini MA J Biol Chem. 2010 Feb 19;285(8):5188-95. Epub 2009 Nov 30. PMID:19948665<ref>PMID:19948665</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3hij" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Dihydrodipicolinate synthase|Dihydrodipicolinate synthase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | [[Category: Large Structures]] | ||
[[ | [[Category: Dobson, R C.J]] | ||
[[Category: Perugini, M A]] | |||
== | [[Category: Scally, S W]] | ||
< | [[Category: Voss, J E]] | ||
[[Category: | |||
[[Category: Dobson, R C.J | |||
[[Category: Perugini, M A | |||
[[Category: Scally, S W | |||
[[Category: Voss, J E | |||
[[Category: Amino-acid biosynthesis]] | [[Category: Amino-acid biosynthesis]] | ||
[[Category: Diaminopimelate biosynthesis]] | [[Category: Diaminopimelate biosynthesis]] | ||
[[Category: Lyase]] | [[Category: Lyase]] | ||
Latest revision as of 15:48, 23 March 2022
Crystal structure of dihydrodipicolinate synthase from Bacillus anthracis in complex with its substrate, pyruvateCrystal structure of dihydrodipicolinate synthase from Bacillus anthracis in complex with its substrate, pyruvate
Structural highlights
Function[Q81WN7_BACAN] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA) (By similarity).[SAAS:SAAS020625_004_011311][HAMAP-Rule:MF_00418] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedBacillus anthracis is a gram-positive spore-forming bacterium that causes anthrax. With the increased threat of anthrax in biowarfare, there is an urgent need to characterize new antimicrobial targets from B. anthracis. One such target is dihydrodipicolinate synthase (DHDPS), which catalyzes the committed step in the pathway yielding meso-diaminopimelate and lysine. In this study, we employed CD spectroscopy to demonstrate that the thermostability of DHDPS from B. anthracis (Ba-DHDPS) is significantly enhanced in the presence of the substrate, pyruvate. Analytical ultracentrifugation studies show that the tetramer-dimer dissociation constant of the enzyme is 3-fold tighter in the presence of pyruvate compared with the apo form. To examine the significance of this substrate-mediated stabilization phenomenon, a dimeric mutant of Ba-DHDPS (L170E/G191E) was generated and shown to have markedly reduced activity compared with the wild-type tetramer. This demonstrates that the substrate, pyruvate, stabilizes the active form of the enzyme. We next determined the high resolution (2.15 A) crystal structure of Ba-DHDPS in complex with pyruvate (3HIJ) and compared this to the apo structure (1XL9). Structural analyses show that there is a significant (91 A(2)) increase in buried surface area at the tetramerization interface of the pyruvate-bound structure. This study describes a new mechanism for stabilization of the active oligomeric form of an antibiotic target from B. anthracis and reveals an "Achilles heel" that can be exploited in structure-based drug design. Substrate-mediated stabilization of a tetrameric drug target reveals Achilles heel in anthrax.,Voss JE, Scally SW, Taylor NL, Atkinson SC, Griffin MD, Hutton CA, Parker MW, Alderton MR, Gerrard JA, Dobson RC, Dogovski C, Perugini MA J Biol Chem. 2010 Feb 19;285(8):5188-95. Epub 2009 Nov 30. PMID:19948665[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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