5n29

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Current revision (17:58, 8 November 2023) (edit) (undo)
 
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<StructureSection load='5n29' size='340' side='right'caption='[[5n29]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
<StructureSection load='5n29' size='340' side='right'caption='[[5n29]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5n29]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Tryb9 Tryb9]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N29 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5N29 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5n29]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Trypanosoma_brucei_gambiense_DAL972 Trypanosoma brucei gambiense DAL972]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5N29 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5N29 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=8JB:(2~{R})-2-AZANYL-3-[[(5~{S})-5-[(1~{S})-1-AZANYL-2-OXIDANYL-2-OXIDANYLIDENE-ETHYL]-4,5-DIHYDRO-1,2-OXAZOL-3-YL]SULFANYL]PROPANOIC+ACID'>8JB</scene></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8JB:(2~{R})-2-AZANYL-3-[[(5~{S})-5-[(1~{S})-1-AZANYL-2-OXIDANYL-2-OXIDANYLIDENE-ETHYL]-4,5-DIHYDRO-1,2-OXAZOL-3-YL]SULFANYL]PROPANOIC+ACID'>8JB</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2wzt|2wzt]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5n29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n29 OCA], [https://pdbe.org/5n29 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5n29 RCSB], [https://www.ebi.ac.uk/pdbsum/5n29 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5n29 ProSAT]</span></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TbgDal_I580 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=679716 TRYB9])</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/CTP_synthase_(glutamine_hydrolyzing) CTP synthase (glutamine hydrolyzing)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.4.2 6.3.4.2] </span></td></tr>
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<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=5n29 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5n29 OCA], [http://pdbe.org/5n29 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5n29 RCSB], [http://www.ebi.ac.uk/pdbsum/5n29 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5n29 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/C9ZI73_TRYB9 C9ZI73_TRYB9]] Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen.[RuleBase:RU810713]
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[https://www.uniprot.org/uniprot/C9ZI73_TRYB9 C9ZI73_TRYB9] Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen.[RuleBase:RU810713]
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Aldo-keto reductases (AKRs) are a large superfamily of NADPH-dependent enzymes that catalyze the reduction of aldehydes, aldoses, dicarbonyls, steroids, and monosaccharides. While their precise physiological role is generally unknown, AKRs are nevertheless involved in the detoxification of a broad range of toxic metabolites. Mycobacteria contain a number of AKRs, the majority of which are uncharacterised. Here, we report the 1.9 and 1.6 A resolution structures of the apoenzyme and NADPH-bound forms, respectively, of an AKR (MSMEG_2407) from Mycobacterium smegmatis, a close homologue of the M. tuberculosis enzyme Rv2971, whose function is essential to this bacterium. MSMEG_2407 adopted the triosephosphate isomerase (alpha/beta)(8)-barrel fold exhibited by other AKRs. MSMEG_2407 (AKR5H1) bound NADPH via an induced-fit mechanism, in which the NADPH was ligated in an extended fashion. Polar-mediated interactions dominated the interactions with the cofactor, which is atypical of the mode of NADPH binding within the AKR family. Moreover, the nicotinamide ring of NADPH was disordered, and this was attributed to the lack of an "AKR-conserved" bulky residue within the nicotinamide-binding cavity of MSMEG_2407. Enzymatic characterisation of MSMEG_2407 and Rv2971 identified dicarbonyls as a preferred substrate family for hydrolysis, and the frontline antituberculosis drug isoniazid (INH) was shown to inhibit the enzyme activity of both recombinant MSMEG_2407 and Rv2971. However, differences between the affinities of MSMEG_2407 and Rv2971 for dicarbonyls and INH were observed, and this was attributable to amino acid substitutions within the cofactor- and substrate-binding sites. The structures of MSMEG_2407 and the accompanying biochemical characterisation of MSMEG_2407 and Rv2971 provide insight into the structure and function of AKRs from mycobacteria.
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The natural product acivicin inhibits the glutaminase activity of cytidine triphosphate (CTP) synthetase and is a potent lead compound for drug discovery in the area of neglected tropical diseases, specifically trypanosomaisis. A 2.1-A-resolution crystal structure of the acivicin adduct with the glutaminase domain from Trypanosoma brucei CTP synthetase has been deposited in the RCSB Protein Data Bank (PDB) and provides a template for structure-based approaches to design new inhibitors. However, our assessment of that data identified deficiencies in the model. We now report an improved and corrected inhibitor structure with changes to the chirality at one position, the orientation and covalent structure of the isoxazoline moiety, and the location of a chloride ion in an oxyanion binding site that is exploited during catalysis. The model is now in agreement with established chemical principles and allows an accurate description of molecular recognition of the ligand and the mode of binding in a potentially valuable drug target.
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Crystal structure and comparative functional analyses of a Mycobacterium aldo-keto reductase.,Scoble J, McAlister AD, Fulton Z, Troy S, Byres E, Vivian JP, Brammananth R, Wilce MC, Le Nours J, Zaker-Tabrizi L, Coppel RL, Crellin PK, Rossjohn J, Beddoe T J Mol Biol. 2010 Apr 23;398(1):26-39. Epub 2010 Feb 25. PMID:20188740<ref>PMID:20188740</ref>
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An Improved Model of the Trypanosoma brucei CTP Synthetase Glutaminase Domain-Acivicin Complex.,Oliveira de Souza J, Dawson A, Hunter WN ChemMedChem. 2017 Mar 23. doi: 10.1002/cmdc.201700118. PMID:28333400<ref>PMID:28333400</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</StructureSection>
</StructureSection>
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Tryb9]]
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[[Category: Trypanosoma brucei gambiense DAL972]]
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[[Category: Dawson, A]]
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[[Category: Dawson A]]
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[[Category: Hunter, W]]
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[[Category: Hunter W]]
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[[Category: Souza, J de]]
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[[Category: De Souza J]]
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[[Category: Ctp synthase]]
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[[Category: Ligase]]
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Current revision

An improved model of the Trypanosoma brucei CTP synthase glutaminase domain:acivicin complex.

PDB ID 5n29

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