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| | ==biomimetic design results in a potent allosteric inhibitor of dihydrodipicolinate synthase from Campylobacter jejuni== | | ==biomimetic design results in a potent allosteric inhibitor of dihydrodipicolinate synthase from Campylobacter jejuni== |
| - | <StructureSection load='5f1u' size='340' side='right' caption='[[5f1u]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='5f1u' size='340' side='right'caption='[[5f1u]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5f1u]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"campylobacter_fetus_subsp._jejuni"_smibert_1974 "campylobacter fetus subsp. jejuni" smibert 1974]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5F1U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5f1u]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Campylobacter_jejuni Campylobacter jejuni]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5F1U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5F1U FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3VN:(2R,5R)-2,5-DIAMINO-2,5-BIS(4-AMINOBUTYL)HEXANEDIOIC+ACID'>3VN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5f1v|5f1v]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3VN:(2R,5R)-2,5-DIAMINO-2,5-BIS(4-AMINOBUTYL)HEXANEDIOIC+ACID'>3VN</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</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=197 "Campylobacter fetus subsp. jejuni" Smibert 1974])</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=5f1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f1u OCA], [https://pdbe.org/5f1u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5f1u RCSB], [https://www.ebi.ac.uk/pdbsum/5f1u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5f1u ProSAT]</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=5f1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5f1u OCA], [http://pdbe.org/5f1u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5f1u RCSB], [http://www.ebi.ac.uk/pdbsum/5f1u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5f1u ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/DAPA_CAMJE DAPA_CAMJE]] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).[HAMAP-Rule:MF_00418] | + | [https://www.uniprot.org/uniprot/DAPA_CAMJE DAPA_CAMJE] Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).[HAMAP-Rule:MF_00418] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5f1u" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5f1u" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Dihydrodipicolinate synthase|Dihydrodipicolinate synthase]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Campylobacter fetus subsp. jejuni smibert 1974]] | + | [[Category: Campylobacter jejuni]] |
| - | [[Category: 4-hydroxy-tetrahydrodipicolinate synthase]] | + | [[Category: Large Structures]] |
| - | [[Category: Conly, C J.T]] | + | [[Category: Conly CJT]] |
| - | [[Category: Palmer, D R.J]] | + | [[Category: Palmer DRJ]] |
| - | [[Category: Sanders, D A.R]] | + | [[Category: Sanders DAR]] |
| - | [[Category: Aldolase]]
| + | |
| - | [[Category: Lyase-lyase inhibitor complex]]
| + | |
| - | [[Category: Schiff-base]]
| + | |
| - | [[Category: Tim barrel]]
| + | |
| Structural highlights
5f1u is a 4 chain structure with sequence from Campylobacter jejuni. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.35Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
DAPA_CAMJE Catalyzes the condensation of (S)-aspartate-beta-semialdehyde [(S)-ASA] and pyruvate to 4-hydroxy-tetrahydrodipicolinate (HTPA).[HAMAP-Rule:MF_00418]
Publication Abstract from PubMed
Dihydrodipicolinate synthase (DHDPS), an enzyme required for bacterial peptidoglycan biosynthesis, catalyzes the condensation of pyruvate and beta-aspartate semialdehyde (ASA) to form a cyclic product which dehydrates to form dihydrodipicolinate. DHDPS has, for several years, been considered a putative target for novel antibiotics. We have designed the first potent inhibitor of this enzyme by mimicking its natural allosteric regulation by lysine, and obtained a crystal structure of the protein-inhibitor complex at 2.2 A resolution. This novel inhibitor, which we named "bislysine", resembles two lysine molecules linked by an ethylene bridge between the alpha-carbon atoms. Bislysine is a mixed partial inhibitor with respect to the first substrate, pyruvate, and a noncompetitive partial inhibitor with respect to ASA, and binds to all forms of the enzyme with a Ki near 200 nM, more than 300 times more tightly than lysine. Hill plots show that the inhibition is cooperative, indicating that the allosteric sites are not independent despite being located on opposite sides of the protein tetramer, separated by approximately 50 A. A mutant enzyme resistant to lysine inhibition, Y110F, is strongly inhibited by this novel inhibitor, suggesting this may be a promising strategy for antibiotic development.
Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni.,Skovpen YV, Conly CJ, Sanders DA, Palmer DR J Am Chem Soc. 2016 Feb 17;138(6):2014-20. doi: 10.1021/jacs.5b12695. Epub 2016, Feb 2. PMID:26836694[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Skovpen YV, Conly CJ, Sanders DA, Palmer DR. Biomimetic Design Results in a Potent Allosteric Inhibitor of Dihydrodipicolinate Synthase from Campylobacter jejuni. J Am Chem Soc. 2016 Feb 17;138(6):2014-20. doi: 10.1021/jacs.5b12695. Epub 2016, Feb 2. PMID:26836694 doi:http://dx.doi.org/10.1021/jacs.5b12695
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