2p4j: Difference between revisions
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<StructureSection load='2p4j' size='340' side='right'caption='[[2p4j]], [[Resolution|resolution]] 2.50Å' scene=''> | <StructureSection load='2p4j' size='340' side='right'caption='[[2p4j]], [[Resolution|resolution]] 2.50Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2p4j]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[2p4j]] 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=2P4J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2P4J FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=23I:N-[(1S,2S,4R)-2-HYDROXY-1-ISOBUTYL-5-({(1S)-1-[(ISOPROPYLAMINO)CARBONYL]-2-METHYLPROPYL}AMINO)-4-METHYL-5-OXOPENTYL]-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]ISOPHTHALAMIDE'>23I</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.5Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=23I:N-[(1S,2S,4R)-2-HYDROXY-1-ISOBUTYL-5-({(1S)-1-[(ISOPROPYLAMINO)CARBONYL]-2-METHYLPROPYL}AMINO)-4-METHYL-5-OXOPENTYL]-5-[METHYL(METHYLSULFONYL)AMINO]-N-[(1R)-1-PHENYLETHYL]ISOPHTHALAMIDE'>23I</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=2p4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p4j OCA], [https://pdbe.org/2p4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p4j RCSB], [https://www.ebi.ac.uk/pdbsum/2p4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p4j ProSAT]</span></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=2p4j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2p4j OCA], [https://pdbe.org/2p4j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2p4j RCSB], [https://www.ebi.ac.uk/pdbsum/2p4j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2p4j ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ghosh AK]] | |||
[[Category: Ghosh | [[Category: Hong L]] | ||
[[Category: Hong | [[Category: Tang J]] | ||
[[Category: Tang | |||
Latest revision as of 13:54, 30 August 2023
Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3Crystal structure of beta-secretase bond to an inhibitor with Isophthalamide Derivatives at P2-P3
Structural highlights
FunctionBACE1_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedStructure-based design and synthesis of a number of potent and selective memapsin 2 inhibitors are described. These inhibitors were designed based upon the X-ray structure of memapsin 2-bound inhibitor 3 that incorporates methylsulfonyl alanine as the P2-ligand and a substituted pyrazole as the P3-ligand. Of particular importance, we examined the ability of the substituted isophthalic acid amide derivative to mimic the key interactions in the S2-S3 regions of the enzyme active sites of 3-bound memapsin 2. We investigated various substituted phenylethyl, alpha-methylbenzyl, and oxazolylmethyl groups as the P3-ligands. A number of inhibitors exhibited very potent inhibitory activity against mempasin 2 and good selectivity against memapsin 1. Inhibitor 5d has shown low nanomolar enzyme inhibitory potency (Ki=1.1 nM) and very good cellular inhibitory activity (IC50=39 nM). Furthermore, in a preliminary study, inhibitor 5d has shown 30% reduction of Abeta40 production in transgenic mice after a single intraperitoneal administration (8 mg/kg). A protein-ligand X-ray crystal structure of 5d-bound memapsin 2 provided vital molecular insight that can serve as an important guide to further design of novel inhibitors. Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands.,Ghosh AK, Kumaragurubaran N, Hong L, Kulkarni SS, Xu X, Chang W, Weerasena V, Turner R, Koelsch G, Bilcer G, Tang J J Med Chem. 2007 May 17;50(10):2399-407. Epub 2007 Apr 14. PMID:17432843[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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