7y5t: Difference between revisions
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The entry | ==CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560== | ||
<StructureSection load='7y5t' size='340' side='right'caption='[[7y5t]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7y5t]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7Y5T OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7Y5T FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.9Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CLR:CHOLESTEROL'>CLR</scene>, <scene name='pdbligand=IGD:~{N}-[4-[2,5-bis(fluoranyl)phenyl]-4-(4-chlorophenyl)sulfonyl-cyclohexyl]-1,1,1-tris(fluoranyl)methanesulfonamide'>IGD</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PC1:1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE'>PC1</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=7y5t FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7y5t OCA], [https://pdbe.org/7y5t PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7y5t RCSB], [https://www.ebi.ac.uk/pdbsum/7y5t PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7y5t ProSAT]</span></td></tr> | |||
</table> | |||
== Disease == | |||
[https://www.uniprot.org/uniprot/NICA_HUMAN NICA_HUMAN] Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/NICA_HUMAN NICA_HUMAN] Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Inhibition of gamma-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of gamma-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing gamma-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 A. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting gamma-secretase. | |||
Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.,Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y Nat Commun. 2022 Oct 22;13(1):6299. doi: 10.1038/s41467-022-33817-5. PMID:36272978<ref>PMID:36272978</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 7y5t" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Gamma secretase|Gamma secretase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Guo X]] | |||
[[Category: Jia B]] | |||
[[Category: Jin C]] | |||
[[Category: Jing D]] | |||
[[Category: Lei J]] | |||
[[Category: Shi Y]] | |||
[[Category: Wang J]] | |||
[[Category: Wang Y]] | |||
[[Category: Yan C]] | |||
[[Category: Zhou J]] | |||
[[Category: Zhou R]] | |||
Latest revision as of 14:50, 30 October 2024
CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560
Structural highlights
DiseaseNICA_HUMAN Hidradenitis suppurativa. The disease is caused by mutations affecting the gene represented in this entry. FunctionNICA_HUMAN Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). It probably represents a stabilizing cofactor required for the assembly of the gamma-secretase complex. Publication Abstract from PubMedInhibition of gamma-secretase activity represents a potential therapeutic strategy for Alzheimer's disease (AD). MRK-560 is a selective inhibitor with higher potency for Presenilin 1 (PS1) than for PS2, the two isoforms of the catalytic subunit of gamma-secretase, although the underlying mechanism remains elusive. Here we report the cryo-electron microscopy (cryo-EM) structures of PS1 and PS2-containing gamma-secretase complexes with and without MRK-560 at overall resolutions of 2.9-3.4 A. MRK-560 occupies the substrate binding site of PS1, but is invisible in PS2. Structural comparison identifies Thr281 and Leu282 in PS1 to be the determinant for isoform-dependent sensitivity to MRK-560, which is confirmed by swapping experiment between PS1 and PS2. By revealing the mechanism for isoform-selective inhibition of presenilin, our work may facilitate future drug discovery targeting gamma-secretase. Molecular basis for isoform-selective inhibition of presenilin-1 by MRK-560.,Guo X, Wang Y, Zhou J, Jin C, Wang J, Jia B, Jing D, Yan C, Lei J, Zhou R, Shi Y Nat Commun. 2022 Oct 22;13(1):6299. doi: 10.1038/s41467-022-33817-5. PMID:36272978[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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