2aaz: Difference between revisions
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==Cryptococcus neoformans thymidylate synthase complexed with substrate and an antifolate== | |||
<StructureSection load='2aaz' size='340' side='right'caption='[[2aaz]], [[Resolution|resolution]] 2.08Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2aaz]] is a 16 chain structure with sequence from [https://en.wikipedia.org/wiki/Cryptococcus_neoformans Cryptococcus neoformans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2AAZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2AAZ FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.08Å, 4 models</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CB3:10-PROPARGYL-5,8-DIDEAZAFOLIC+ACID'>CB3</scene>, <scene name='pdbligand=UMP:2-DEOXYURIDINE+5-MONOPHOSPHATE'>UMP</scene></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=2aaz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2aaz OCA], [https://pdbe.org/2aaz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2aaz RCSB], [https://www.ebi.ac.uk/pdbsum/2aaz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2aaz ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/TYSY_CRYNJ TYSY_CRYNJ] | |||
== 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/aa/2aaz_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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=2aaz ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3''-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery. | |||
The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.,Finer-Moore JS, Anderson AC, O'Neil RH, Costi MP, Ferrari S, Krucinski J, Stroud RM Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1320-34. Epub 2005, Sep 28. PMID:16204883<ref>PMID:16204883</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 2aaz" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Thymidylate synthase|Thymidylate synthase]] | *[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Cryptococcus neoformans]] | [[Category: Cryptococcus neoformans]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Anderson | [[Category: Anderson AC]] | ||
[[Category: Costi | [[Category: Costi MP]] | ||
[[Category: Ferrari | [[Category: Ferrari S]] | ||
[[Category: Finer-Moore | [[Category: Finer-Moore JS]] | ||
[[Category: Krucinski | [[Category: Krucinski J]] | ||
[[Category: Neil | [[Category: O'Neil RH]] | ||
[[Category: Stroud | [[Category: Stroud RM]] | ||
Latest revision as of 10:33, 9 October 2024
Cryptococcus neoformans thymidylate synthase complexed with substrate and an antifolateCryptococcus neoformans thymidylate synthase complexed with substrate and an antifolate
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe ternary complex crystal structures of Cryptococcus neoformans and Escherichia coli thymidylate synthase (TS) suggest mechanisms of species-specific inhibition of a highly conserved protein. The 2.1 Angstrom structure of C. neoformans TS cocrystallized with substrate and the cofactor analog CB3717 shows that the binding sites for substrate and cofactor are highly conserved with respect to human TS, but that the structure of the cofactor-binding site of C. neoformans TS is less constrained by surrounding residues. This feature might allow C. neoformans TS to form TS-dUMP-inhibitor complexes with a greater range of antifolates than human TS. 3',3-Dibromophenol-4-chloro-1,8-naphthalein (GA9) selectively inhibits both E. coli TS and C. neoformans TS (K(i) = 4 microM) over human TS (K(i) >> 245 microM). The E. coli TS-dUMP-GA9 complex is in an open conformation, similar to that of the apoenzyme crystal structure. The GA9-binding site overlaps the binding site of the pABA-glutamyl moiety of the cofactor. The fact that human apoTS can adopt an unusual fold in which the GA9-binding site is disordered may explain the poor affinity of GA9 for the human enzyme. These observations highlight the critical need to incorporate multiple target conformations in any computational attempt to facilitate drug discovery. The structure of Cryptococcus neoformans thymidylate synthase suggests strategies for using target dynamics for species-specific inhibition.,Finer-Moore JS, Anderson AC, O'Neil RH, Costi MP, Ferrari S, Krucinski J, Stroud RM Acta Crystallogr D Biol Crystallogr. 2005 Oct;61(Pt 10):1320-34. Epub 2005, Sep 28. PMID:16204883[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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