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6hl7

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==Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with mutated active site (R109A/K138A) and N-carbamoyl-L-phosphate bound==
==Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with mutated active site (R109A/K138A) and N-carbamoyl-L-phosphate bound==
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<StructureSection load='6hl7' size='340' side='right' caption='[[6hl7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
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<StructureSection load='6hl7' size='340' side='right'caption='[[6hl7]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6hl7]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HL7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HL7 FirstGlance]. <br>
<table><tr><td colspan='2'>[[6hl7]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Plafa Plafa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6HL7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6HL7 FirstGlance]. <br>
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<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The de novo pyrimidine-biosynthesis pathway of Plasmodium falciparum is a promising target for antimalarial drug discovery. The parasite requires a supply of purines and pyrimidines for growth and proliferation and is unable to take up pyrimidines from the host. Direct (or indirect) inhibition of de novo pyrimidine biosynthesis via dihydroorotate dehydrogenase (PfDHODH), the fourth enzyme of the pathway, has already been shown to be lethal to the parasite. In the second step of the plasmodial pyrimidine-synthesis pathway, aspartate and carbamoyl phosphate are condensed to N-carbamoyl-L-aspartate and inorganic phosphate by aspartate transcarbamoylase (PfATC). In this paper, the 2.5 A resolution crystal structure of PfATC is reported. The space group of the PfATC crystals was determined to be monoclinic P21, with unit-cell parameters a = 87.0, b = 103.8, c = 87.1 A, alpha = 90.0, beta = 117.7, gamma = 90.0 degrees . The presented PfATC model shares a high degree of homology with the catalytic domain of Escherichia coli ATC. There is as yet no evidence of the existence of a regulatory domain in PfATC. Similarly to E. coli ATC, PfATC was modelled as a homotrimer in which each of the three active sites is formed at the oligomeric interface. Each active site comprises residues from two adjacent subunits in the trimer with a high degree of evolutional conservation. Here, the activity loss owing to mutagenesis of the key active-site residues is also described.
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Malaria is a tropical disease that kills about half a million people around the world annually. Enzymatic reactions within pyrimidine biosynthesis have been proven to be essential for Plasmodium proliferation. Here we report on the essentiality of the second enzymatic step of the pyrimidine biosynthesis pathway, catalyzed by aspartate transcarbamoylase (ATC). Crystallization experiments using a double mutant ofPlasmodium falciparum ATC (PfATC) revealed the importance of the mutated residues for enzyme catalysis. Subsequently, this mutant was employed in protein interference assays (PIAs), which resulted in inhibition of parasite proliferation when parasites transfected with the double mutant were cultivated in medium lacking an excess of nutrients, including aspartate. Addition of 5 or 10 mg/L of aspartate to the minimal medium restored the parasites' normal growth rate. In vitro and whole-cell assays in the presence of the compound Torin 2 showed inhibition of specific activity and parasite growth, respectively. In silico analyses revealed the potential binding mode of Torin 2 to PfATC. Furthermore, a transgenic ATC-overexpressing cell line exhibited a 10-fold increased tolerance to Torin 2 compared with control cultures. Taken together, our results confirm the antimalarial activity of Torin 2, suggesting PfATC as a target of this drug and a promising target for the development of novel antimalarials.
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Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum.,Lunev S, Bosch SS, Batista Fde A, Wrenger C, Groves MR Acta Crystallogr F Struct Biol Commun. 2016 Jul 1;72(Pt 7):523-33. doi:, 10.1107/S2053230X16008475. Epub 2016 Jun 22. PMID:27380369<ref>PMID:27380369</ref>
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Molecular Target Validation of Aspartate Transcarbamoylase from Plasmodium falciparum by Torin 2.,Bosch SS, Lunev S, Batista FA, Linzke M, Kronenberger T, Domling ASS, Groves MR, Wrenger C ACS Infect Dis. 2020 Mar 12. doi: 10.1021/acsinfecdis.9b00411. PMID:32129597<ref>PMID:32129597</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: Aspartate carbamoyltransferase]]
[[Category: Aspartate carbamoyltransferase]]
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[[Category: Large Structures]]
[[Category: Plafa]]
[[Category: Plafa]]
[[Category: Bosch, S S]]
[[Category: Bosch, S S]]

Revision as of 10:12, 18 March 2020

Crystal structure of truncated aspartate transcarbamoylase from Plasmodium falciparum with mutated active site (R109A/K138A) and N-carbamoyl-L-phosphate bound

PDB ID 6hl7

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