1nhg: Difference between revisions

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CRYSTAL STRUCTURE ANALYSIS OF PLASMODIUM FALCIPARUM ENOYL-ACYL-CARRIER-PROTEIN REDUCTASE WITH TRICLOSAN

OverviewOverview

The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.

About this StructureAbout this Structure

1NHG is a Protein complex structure of sequences from Plasmodium falciparum with and as ligands. Active as [acyl-carrier-protein_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number 1.3.1.9 Full crystallographic information is available from OCA.

ReferenceReference

Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase., Perozzo R, Kuo M, Sidhu AS, Valiyaveettil JT, Bittman R, Jacobs WR Jr, Fidock DA, Sacchettini JC, J Biol Chem. 2002 Apr 12;277(15):13106-14. Epub 2002 Jan 15. PMID:11792710 [[Category: Enoyl-[acyl-carrier-protein] reductase (NADH)]]

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 '''CRYSTAL STRUCTURE ANALYSIS OF PLASMODIUM FALCIPARUM ENOYL-ACYL-CARRIER-PROTEIN REDUCTASE WITH TRICLOSAN'''<br />
 ==Overview==
-The human malaria parasite Plasmodium falciparum synthesizes fatty acids, using a type II pathway that is absent in humans. The final step in fatty, acid elongation is catalyzed by enoyl acyl carrier protein reductase, a, validated antimicrobial drug target. Here, we report the cloning and, expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique, parasite apicoplast. Purified PfENR was crystallized, and its structure, resolved as a binary complex with NADH, a ternary complex with triclosan, and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and, 2 with NADH. Novel structural features were identified in the PfENR, binding loop region that most closely resembled bacterial homologs;, elsewhere the protein was similar to ENR from the plant Brassica napus, (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2, killed multidrug-resistant strains of intra-erythrocytic P. falciparum, parasites at sub to low micromolar concentrations in vitro. These data, define the structural basis of triclosan binding to PfENR and will, facilitate structure-based optimization of PfENR inhibitors.
+The human malaria parasite Plasmodium falciparum synthesizes fatty acids using a type II pathway that is absent in humans. The final step in fatty acid elongation is catalyzed by enoyl acyl carrier protein reductase, a validated antimicrobial drug target. Here, we report the cloning and expression of the P. falciparum enoyl acyl carrier protein reductase gene, which encodes a 50-kDa protein (PfENR) predicted to target to the unique parasite apicoplast. Purified PfENR was crystallized, and its structure resolved as a binary complex with NADH, a ternary complex with triclosan and NAD(+), and as ternary complexes bound to the triclosan analogs 1 and 2 with NADH. Novel structural features were identified in the PfENR binding loop region that most closely resembled bacterial homologs; elsewhere the protein was similar to ENR from the plant Brassica napus (root mean square for Calphas, 0.30 A). Triclosan and its analogs 1 and 2 killed multidrug-resistant strains of intra-erythrocytic P. falciparum parasites at sub to low micromolar concentrations in vitro. These data define the structural basis of triclosan binding to PfENR and will facilitate structure-based optimization of PfENR inhibitors.
 ==About this Structure==
-NHG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with NAD and TCL as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1NHG OCA].
+NHG is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Plasmodium_falciparum Plasmodium falciparum] with <scene name='pdbligand=NAD:'>NAD</scene> and <scene name='pdbligand=TCL:'>TCL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NHG OCA].
 ==Reference==
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 [[Category: Protein complex]]
 [[Category: Bittman, R.]]
-[[Category: Fidock, D.A.]]
+[[Category: Fidock, D A.]]
-[[Category: Jr., W.R.Jacobs.]]
+[[Category: Jr., W R.Jacobs.]]
 [[Category: Kuo, M.]]
 [[Category: Perozzo, R.]]
-[[Category: Sacchettini, J.C.]]
+[[Category: Sacchettini, J C.]]
-[[Category: Sidhu, A.S.]]
+[[Category: Sidhu, A S.]]
-[[Category: Valiyaveettil, J.T.]]
+[[Category: Valiyaveettil, J T.]]
 [[Category: NAD]]
 [[Category: TCL]]
@@ Line 28: / Line 28: @@
 [[Category: short chain dehydrogenase reductase]]
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