6y37: Difference between revisions
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==CCAAT-binding complex from Aspergillus nidulans with cccA DNA== | ==CCAAT-binding complex from Aspergillus nidulans with cccA DNA== | ||
<StructureSection load='6y37' size='340' side='right'caption='[[6y37]]' scene=''> | <StructureSection load='6y37' size='340' side='right'caption='[[6y37]], [[Resolution|resolution]] 2.20Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y37 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y37 FirstGlance]. <br> | <table><tr><td colspan='2'>[[6y37]] is a 5 chain structure with sequence from [http://en.wikipedia.org/wiki/Aspergillus_nidulans Aspergillus nidulans]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y37 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y37 FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y37 OCA], [http://pdbe.org/6y37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y37 RCSB], [http://www.ebi.ac.uk/pdbsum/6y37 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y37 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4g91|4g91]], [[4g92|4g92]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ANIA_07545 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=227321 Aspergillus nidulans]), ANIA_04034 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=227321 Aspergillus nidulans]), AN6492.2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=227321 Aspergillus nidulans])</td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y37 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y37 OCA], [http://pdbe.org/6y37 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y37 RCSB], [http://www.ebi.ac.uk/pdbsum/6y37 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y37 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Azoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole-resistant clinical Aspergillus fumigatus isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapE(P88L) mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the cyp51A gene, which encodes the target of azoles, the 14-alpha sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists cyp51A repression in low-iron environments and that this iron-dependent effect is lost in the HapE(P88L) mutant. Altogether, these results indicate that the mutation HapE(P88L) confers increased resistance to azoles compared with wt A. fumigatus, particularly in low-iron clinical niches such as the lung. | |||
Structural basis of HapE(P88L)-linked antifungal triazole resistance in Aspergillus fumigatus.,Hortschansky P, Misslinger M, Morl J, Gsaller F, Bromley MJ, Brakhage AA, Groll M, Haas H, Huber EM Life Sci Alliance. 2020 May 28;3(7). pii: 3/7/e202000729. doi:, 10.26508/lsa.202000729. Print 2020 Jul. PMID:32467317<ref>PMID:32467317</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6y37" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Aspergillus nidulans]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Groll M]] | [[Category: Groll, M]] | ||
[[Category: Huber | [[Category: Huber, E M]] | ||
[[Category: Heterotrimer]] | |||
[[Category: Histone fold]] | |||
[[Category: Protein:dna complex]] | |||
[[Category: Transcription]] | |||
[[Category: Transcription factor]] | |||
Revision as of 09:53, 10 June 2020
CCAAT-binding complex from Aspergillus nidulans with cccA DNACCAAT-binding complex from Aspergillus nidulans with cccA DNA
Structural highlights
Publication Abstract from PubMedAzoles are first-line therapeutics for human and plant fungal infections, but their broad use has promoted the development of resistances. Recently, a pan-azole-resistant clinical Aspergillus fumigatus isolate was identified to carry the mutation P88L in subunit HapE of the CCAAT-binding complex (CBC), a conserved eukaryotic transcription factor. Here, we define the mechanistic basis for resistance in this isolate by showing that the HapE(P88L) mutation interferes with the CBC's ability to bend and sense CCAAT motifs. This failure leads to transcriptional derepression of the cyp51A gene, which encodes the target of azoles, the 14-alpha sterol demethylase Cyp51A, and ultimately causes drug resistance. In addition, we demonstrate that the CBC-associated transcriptional regulator HapX assists cyp51A repression in low-iron environments and that this iron-dependent effect is lost in the HapE(P88L) mutant. Altogether, these results indicate that the mutation HapE(P88L) confers increased resistance to azoles compared with wt A. fumigatus, particularly in low-iron clinical niches such as the lung. Structural basis of HapE(P88L)-linked antifungal triazole resistance in Aspergillus fumigatus.,Hortschansky P, Misslinger M, Morl J, Gsaller F, Bromley MJ, Brakhage AA, Groll M, Haas H, Huber EM Life Sci Alliance. 2020 May 28;3(7). pii: 3/7/e202000729. doi:, 10.26508/lsa.202000729. Print 2020 Jul. PMID:32467317[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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