4y6k: Difference between revisions

Revision as of 08:00, 3 May 2023

Complex structure of presenilin homologue PSH bound to an inhibitor

Structural highlights

4y6k is a 4 chain structure with sequence from Methanoculleus marisnigri JR1. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	4B5
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

A3CWV0_METMJ

Publication Abstract from PubMed

Aberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Abeta42, Abeta40, and Abeta38. The molar ratio of the cleavage products Abeta42 over Abeta40 by PSH is nearly identical to that by gamma-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the Abeta42/Abeta40 ratio. Structural analysis reveals association of a known gamma-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of gamma-secretase.

Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.,Dang S, Wu S, Wang J, Li H, Huang M, He W, Li YM, Wong CC, Shi Y Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201502150. PMID:25733893^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dang S, Wu S, Wang J, Li H, Huang M, He W, Li YM, Wong CC, Shi Y. Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH. Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201502150. PMID:25733893 doi:https://dx.doi.org/10.1073/pnas.1502150112

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Dang S, Wu S, Wang J, Li H, Huang M, He W, Li YM, Wong CC, Shi Y. Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH. Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201502150. PMID:25733893 doi:https://dx.doi.org/10.1073/pnas.1502150112

[1]

@@ Line 3: / Line 3: @@
 <StructureSection load='4y6k' size='340' side='right'caption='[[4y6k]], [[Resolution|resolution]] 3.85&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4y6k]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Metmj Metmj]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y6K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y6K FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4y6k]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Methanoculleus_marisnigri_JR1 Methanoculleus marisnigri JR1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y6K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y6K FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4B5:N-{(2R,4S,5S)-2-BENZYL-5-[(TERT-BUTOXYCARBONYL)AMINO]-4-HYDROXY-6-PHENYLHEXANOYL}-L-LEUCYL-L-PHENYLALANINAMIDE'>4B5</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4B5:N-{(2R,4S,5S)-2-BENZYL-5-[(TERT-BUTOXYCARBONYL)AMINO]-4-HYDROXY-6-PHENYLHEXANOYL}-L-LEUCYL-L-PHENYLALANINAMIDE'>4B5</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Memar_1924 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=368407 METMJ])</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=4y6k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y6k OCA], [https://pdbe.org/4y6k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y6k RCSB], [https://www.ebi.ac.uk/pdbsum/4y6k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y6k ProSAT]</span></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=4y6k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y6k OCA], [http://pdbe.org/4y6k PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y6k RCSB], [http://www.ebi.ac.uk/pdbsum/4y6k PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4y6k ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/A3CWV0_METMJ A3CWV0_METMJ]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 23: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Metmj]]
+[[Category: Methanoculleus marisnigri JR1]]
-[[Category: Dang, S]]
+[[Category: Dang S]]
-[[Category: Shi, Y]]
+[[Category: Shi Y]]
-[[Category: Wang, J]]
+[[Category: Wang J]]
-[[Category: Wu, S]]
+[[Category: Wu S]]
-[[Category: Complex]]
-[[Category: Inhibitor]]
-[[Category: Membrane protein-inhibitor complex]]

4y6k: Difference between revisions

Revision as of 08:00, 3 May 2023

Complex structure of presenilin homologue PSH bound to an inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

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