View source for 7t09


==Cryptococcus neoformans protein farnesyltransferase in complex with FPP and inhibitor 2d==
<StructureSection load='7t09' size='340' side='right'caption='[[7t09]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7t09]] is a 2 chain structure with sequence from [https://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=7T09 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T09 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]] 1.984&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3FX:(2R)-3-(CYCLOHEXYLAMINO)-2-HYDROXYPROPANE-1-SULFONIC+ACID'>3FX</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=XMV:4-{[5-({(2S)-2-butyl-5-oxo-4-[3-(trifluoromethoxy)phenyl]piperazin-1-yl}methyl)-1H-imidazol-1-yl]methyl}benzonitrile'>XMV</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=7t09 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t09 OCA], [https://pdbe.org/7t09 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t09 RCSB], [https://www.ebi.ac.uk/pdbsum/7t09 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t09 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/J9VSJ6_CRYNH J9VSJ6_CRYNH] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Infections by fungal pathogens are difficult to treat due to a paucity of antifungals and emerging resistances. Next-generation antifungals therefore are needed urgently. We have developed compounds that prevent farnesylation of Cryptoccoccus neoformans Ras protein by inhibiting protein farnesyltransferase with 3-4 nanomolar affinities. Farnesylation directs Ras to the cell membrane and is required for infectivity of this lethal pathogenic fungus. Our high-affinity compounds inhibit fungal growth with 3-6 micromolar minimum inhibitory concentrations (MICs), 4- to 8-fold better than Fluconazole, an antifungal commonly used in the clinic. Compounds bound with distinct inhibition mechanisms at two alternative, partially overlapping binding sites, accessed via different inhibitor conformations. We showed that antifungal potency depends critically on the selected inhibition mechanism because this determines the efficacy of an inhibitor at low in vivo levels of enzyme and farnesyl substrate. We elucidated how chemical modifications of the antifungals encode desired inhibitor conformation and concomitant inhibitory mechanism.

Structure-Guided Discovery of Potent Antifungals that Prevent Ras Signaling by Inhibiting Protein Farnesyltransferase.,Wang Y, Xu F, Nichols CB, Shi Y, Hellinga HW, Alspaugh JA, Distefano MD, Beese LS J Med Chem. 2022 Oct 11. doi: 10.1021/acs.jmedchem.2c00902. PMID:36218371<ref>PMID:36218371</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7t09" style="background-color:#fffaf0;"></div>

==See Also==
*[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Cryptococcus neoformans var. grubii H99]]
[[Category: Large Structures]]
[[Category: Beese LS]]
[[Category: Shi Y]]
[[Category: Wang Y]]