5v4l: Difference between revisions
New page: '''Unreleased structure''' The entry 5v4l is ON HOLD Authors: Description: Category: Unreleased Structures |
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==Cryptococcus neoformans adenylosuccinate lyase== | |||
<StructureSection load='5v4l' size='340' side='right'caption='[[5v4l]], [[Resolution|resolution]] 2.10Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5v4l]] is a 4 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=5V4L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V4L 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]] 2.1Å</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=5v4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v4l OCA], [https://pdbe.org/5v4l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v4l RCSB], [https://www.ebi.ac.uk/pdbsum/5v4l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v4l ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/J9VSX1_CRYNH J9VSX1_CRYNH] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13Delta mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease. | |||
Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design.,Chitty JL, Blake KL, Blundell RD, Koh YQAE, Thompson M, Robertson AAB, Butler MS, Cooper MA, Kappler U, Williams SJ, Kobe B, Fraser JA J Biol Chem. 2017 Jul 14;292(28):11829-11839. doi: 10.1074/jbc.M117.787994. Epub , 2017 May 30. PMID:28559277<ref>PMID:28559277</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5v4l" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Adenylosuccinate lyase 3D structures|Adenylosuccinate lyase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cryptococcus neoformans]] | |||
[[Category: Large Structures]] | |||
[[Category: Chitty J]] | |||
[[Category: Fraser JA]] | |||
[[Category: Kobe B]] | |||
[[Category: Williams SJ]] | |||
Latest revision as of 16:41, 4 October 2023
Cryptococcus neoformans adenylosuccinate lyaseCryptococcus neoformans adenylosuccinate lyase
Structural highlights
FunctionPublication Abstract from PubMedThere is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13Delta mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS lyase deficiency disease. Cryptococcus neoformans ADS lyase is an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design.,Chitty JL, Blake KL, Blundell RD, Koh YQAE, Thompson M, Robertson AAB, Butler MS, Cooper MA, Kappler U, Williams SJ, Kobe B, Fraser JA J Biol Chem. 2017 Jul 14;292(28):11829-11839. doi: 10.1074/jbc.M117.787994. Epub , 2017 May 30. PMID:28559277[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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