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| | ==Crystal structure of the ternary complex of sp-ASADH with NADP and 1,2,3-Benzenetricarboxylic acid== | | ==Crystal structure of the ternary complex of sp-ASADH with NADP and 1,2,3-Benzenetricarboxylic acid== |
| - | <StructureSection load='4r3n' size='340' side='right' caption='[[4r3n]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='4r3n' size='340' side='right'caption='[[4r3n]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4r3n]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"diplococcus_pneumoniae"_(klein_1884)_weichselbaum_1886 "diplococcus pneumoniae" (klein 1884) weichselbaum 1886]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R3N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R3N FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4r3n]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Streptococcus_pneumoniae Streptococcus pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R3N OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4R3N FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3GQ:BENZENE-1,2,3-TRICARBOXYLIC+ACID'>3GQ</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3GQ:BENZENE-1,2,3-TRICARBOXYLIC+ACID'>3GQ</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAP:NADP+NICOTINAMIDE-ADENINE-DINUCLEOTIDE+PHOSPHATE'>NAP</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">asd ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1313 "Diplococcus pneumoniae" (Klein 1884) Weichselbaum 1886])</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=4r3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r3n OCA], [https://pdbe.org/4r3n PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4r3n RCSB], [https://www.ebi.ac.uk/pdbsum/4r3n PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4r3n 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/Aspartate-semialdehyde_dehydrogenase Aspartate-semialdehyde dehydrogenase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.2.1.11 1.2.1.11] </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=4r3n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r3n OCA], [http://pdbe.org/4r3n PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r3n RCSB], [http://www.ebi.ac.uk/pdbsum/4r3n PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r3n ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/Q8DQ00_STRR6 Q8DQ00_STRR6]] Catalyzes the NADPH-dependent formation of L-aspartate-semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-4-phosphate (By similarity).[HAMAP-Rule:MF_02121] | + | [https://www.uniprot.org/uniprot/Q8DQ00_STRR6 Q8DQ00_STRR6] Catalyzes the NADPH-dependent formation of L-aspartate-semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-4-phosphate (By similarity).[HAMAP-Rule:MF_02121] |
| | <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 4r3n" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4r3n" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aspartate-semialdehyde dehydrogenase 3D structures|Aspartate-semialdehyde dehydrogenase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Aspartate-semialdehyde dehydrogenase]] | + | [[Category: Large Structures]] |
| - | [[Category: Pavlovsky, A G]] | + | [[Category: Streptococcus pneumoniae]] |
| - | [[Category: Viola, R E]] | + | [[Category: Pavlovsky AG]] |
| - | [[Category: Dehydrogenase]] | + | [[Category: Viola RE]] |
| - | [[Category: Nadp binding]]
| + | |
| - | [[Category: Oxidoreductase]]
| + | |
| - | [[Category: Protein-nadp-ligand complex]]
| + | |
| Structural highlights
Function
Q8DQ00_STRR6 Catalyzes the NADPH-dependent formation of L-aspartate-semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-4-phosphate (By similarity).[HAMAP-Rule:MF_02121]
Publication Abstract from PubMed
The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate beta-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme-inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors.
A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway.,Pavlovsky AG, Thangavelu B, Bhansali P, Viola RE Acta Crystallogr D Biol Crystallogr. 2014 Dec 1;70(Pt 12):3244-52. doi:, 10.1107/S1399004714023979. Epub 2014 Nov 22. PMID:25478842[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pavlovsky AG, Thangavelu B, Bhansali P, Viola RE. A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway. Acta Crystallogr D Biol Crystallogr. 2014 Dec 1;70(Pt 12):3244-52. doi:, 10.1107/S1399004714023979. Epub 2014 Nov 22. PMID:25478842 doi:http://dx.doi.org/10.1107/S1399004714023979
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