6f0e: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Structure of yeast Sec14p with a picolinamide compound== | |||
<StructureSection load='6f0e' size='340' side='right' caption='[[6f0e]], [[Resolution|resolution]] 2.60Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f0e]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F0E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F0E FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C8K:~{N}-(1,3-benzodioxol-5-ylmethyl)-5-bromanyl-3-fluoranyl-pyridine-2-carboxamide'>C8K</scene></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=6f0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f0e OCA], [http://pdbe.org/6f0e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f0e RCSB], [http://www.ebi.ac.uk/pdbsum/6f0e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f0e ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/SEC14_YEAST SEC14_YEAST]] Required for transport of secretory proteins from the Golgi complex. Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes in vitro. Essential for viability and secretion. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Invasive fungal infections are accompanied by high mortality rates that range up to 90%. At present, only three different compound classes are available for use in the clinic, and these often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents. Herein, we report the identification of chemically versatile benzamide and picolinamide scaffolds with antifungal properties. Chemogenomic profiling and biochemical assays with purified protein identified Sec14p, the major phosphatidylinositol/phosphatidylcholine transfer protein in Saccharomyces cerevisiae, as the sole essential target for these compounds. A functional variomics screen identified resistance-conferring residues that localized to the lipid-binding pocket of Sec14p. Determination of the X-ray co-crystal structure of a Sec14p-compound complex confirmed binding in this cavity and rationalized both the resistance-conferring residues and the observed structure-activity relationships. Taken together, these findings open new avenues for rational compound optimization and development of novel antifungal agents. | |||
Target Identification and Mechanism of Action of Picolinamide and Benzamide Chemotypes with Antifungal Properties.,Pries V, Nocker C, Khan D, Johnen P, Hong Z, Tripathi A, Keller AL, Fitz M, Perruccio F, Filipuzzi I, Thavam S, Aust T, Riedl R, Ziegler S, Bono F, Schaaf G, Bankaitis VA, Waldmann H, Hoepfner D Cell Chem Biol. 2017 Dec 21. pii: S2451-9456(17)30434-8. doi:, 10.1016/j.chembiol.2017.12.007. PMID:29307839<ref>PMID:29307839</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6f0e" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bono, F]] | [[Category: Bono, F]] | ||
[[Category: Hong, Z]] | [[Category: Hong, Z]] | ||
[[Category: Johnen, P]] | [[Category: Johnen, P]] | ||
[[Category: Schaaf, G]] | |||
[[Category: Antifungal]] | |||
[[Category: Benzamide]] | |||
[[Category: Chemogenomic]] | |||
[[Category: Co-crystal]] | |||
[[Category: Functional variomic]] | |||
[[Category: Lipid binding protein]] | |||
[[Category: Lipid transfer protein]] | |||
[[Category: Picolinamide]] | |||
[[Category: Sec14p]] | |||
[[Category: Target identification]] | |||