3q7a: Difference between revisions
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[[ | ==Cryptococcus neoformans protein farnesyltransferase in complex with FPP and L-778,123== | ||
<StructureSection load='3q7a' size='340' side='right' caption='[[3q7a]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3q7a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Cryptococcus_neoformans_var._grubii_h99 Cryptococcus neoformans var. grubii h99]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3Q7A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3Q7A FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3FX:(2R)-3-(CYCLOHEXYLAMINO)-2-HYDROXYPROPANE-1-SULFONIC+ACID'>3FX</scene>, <scene name='pdbligand=778:4-[(5-{[4-(3-CHLOROPHENYL)-3-OXOPIPERAZIN-1-YL]METHYL}-1H-IMIDAZOL-1-YL)METHYL]BENZONITRILE'>778</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3q73|3q73]], [[3q75|3q75]], [[3q78|3q78]], [[3q79|3q79]], [[3q7f|3q7f]], [[3sfx|3sfx]], [[3sfy|3sfy]]</td></tr> | |||
<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=3q7a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3q7a OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3q7a RCSB], [http://www.ebi.ac.uk/pdbsum/3q7a PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections. | |||
Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens.,Hast MA, Nichols CB, Armstrong SM, Kelly SM, Hellinga HW, Alspaugh JA, Beese LS J Biol Chem. 2011 Oct 7;286(40):35149-62. Epub 2011 Aug 4. PMID:21816822<ref>PMID:21816822</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | ==See Also== | ||
*[[Farnesyltransferase|Farnesyltransferase]] | *[[Farnesyltransferase|Farnesyltransferase]] | ||
== References == | |||
== | <references/> | ||
< | __TOC__ | ||
</StructureSection> | |||
[[Category: Cryptococcus neoformans var. grubii h99]] | [[Category: Cryptococcus neoformans var. grubii h99]] | ||
[[Category: Beese, L S | [[Category: Beese, L S]] | ||
[[Category: Hast, M A | [[Category: Hast, M A]] | ||
[[Category: Protein prenyltransferase]] | [[Category: Protein prenyltransferase]] | ||
[[Category: Transferase-transferase inhibitor complex]] | [[Category: Transferase-transferase inhibitor complex]] | ||
Revision as of 14:31, 9 December 2014
Cryptococcus neoformans protein farnesyltransferase in complex with FPP and L-778,123Cryptococcus neoformans protein farnesyltransferase in complex with FPP and L-778,123
Structural highlights
Publication Abstract from PubMedCryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post-translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate-induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections. Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens.,Hast MA, Nichols CB, Armstrong SM, Kelly SM, Hellinga HW, Alspaugh JA, Beese LS J Biol Chem. 2011 Oct 7;286(40):35149-62. Epub 2011 Aug 4. PMID:21816822[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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