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==LC3A in complex with (3R,4S,5R,6R)-5-hydroxy-6-((4-hydroxy-3-(4-hydroxy-3-isopentylbenzamido)-8-methyl-2-oxo-2H-chromen-7-yl)oxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate== | ==LC3A in complex with (3R,4S,5R,6R)-5-hydroxy-6-((4-hydroxy-3-(4-hydroxy-3-isopentylbenzamido)-8-methyl-2-oxo-2H-chromen-7-yl)oxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate== | ||
<StructureSection load='6tbe' size='340' side='right'caption='[[6tbe]]' scene=''> | <StructureSection load='6tbe' size='340' side='right'caption='[[6tbe]], [[Resolution|resolution]] 1.67Å' 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=6TBE OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6tbe]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6TBE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6TBE FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NOV:NOVOBIOCIN'>NOV</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MAP1LC3A ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6tbe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6tbe OCA], [https://pdbe.org/6tbe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6tbe RCSB], [https://www.ebi.ac.uk/pdbsum/6tbe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6tbe ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://www.uniprot.org/uniprot/MLP3A_HUMAN MLP3A_HUMAN]] Involved in formation of autophagosomal vacuoles (autophagosomes). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs). | |||
Demonstrating Ligandability of the LC3A and LC3B Adapter Interface.,Hartmann M, Huber J, Kramer JS, Heering J, Pietsch L, Stark H, Odadzic D, Bischoff I, Furst R, Schroder M, Akutsu M, Chaikuad A, Dotsch V, Knapp S, Biondi RM, Rogov VV, Proschak E J Med Chem. 2021 Apr 8;64(7):3720-3746. doi: 10.1021/acs.jmedchem.0c01564. Epub, 2021 Mar 26. PMID:33769048<ref>PMID:33769048</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6tbe" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Chaikuad A]] | [[Category: Chaikuad, A]] | ||
[[Category: Hartmann M]] | [[Category: Hartmann, M]] | ||
[[Category: Kramer | [[Category: Kramer, J S]] | ||
[[Category: Pogoryelov D]] | [[Category: Pogoryelov, D]] | ||
[[Category: Proschak E]] | [[Category: Proschak, E]] | ||
[[Category: Autophagy]] | |||
[[Category: Complex]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Lc3a]] | |||
Revision as of 09:24, 1 December 2021
LC3A in complex with (3R,4S,5R,6R)-5-hydroxy-6-((4-hydroxy-3-(4-hydroxy-3-isopentylbenzamido)-8-methyl-2-oxo-2H-chromen-7-yl)oxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamateLC3A in complex with (3R,4S,5R,6R)-5-hydroxy-6-((4-hydroxy-3-(4-hydroxy-3-isopentylbenzamido)-8-methyl-2-oxo-2H-chromen-7-yl)oxy)-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate
Structural highlights
Function[MLP3A_HUMAN] Involved in formation of autophagosomal vacuoles (autophagosomes). Publication Abstract from PubMedAutophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs). Demonstrating Ligandability of the LC3A and LC3B Adapter Interface.,Hartmann M, Huber J, Kramer JS, Heering J, Pietsch L, Stark H, Odadzic D, Bischoff I, Furst R, Schroder M, Akutsu M, Chaikuad A, Dotsch V, Knapp S, Biondi RM, Rogov VV, Proschak E J Med Chem. 2021 Apr 8;64(7):3720-3746. doi: 10.1021/acs.jmedchem.0c01564. Epub, 2021 Mar 26. PMID:33769048[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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