4zpf: Difference between revisions
New page: '''Unreleased structure''' The entry 4zpf is ON HOLD Authors: Orth, P. Description: BACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1... |
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==BACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one== | |||
<StructureSection load='4zpf' size='340' side='right'caption='[[4zpf]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4zpf]] is a 1 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=4ZPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4ZPF FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4QD:8-(3-{[(2S)-1-AMINOPROPAN-2-YL]OXY}BENZYL)-4-(CYCLOHEXYLAMINO)-1-(3-FLUOROPHENYL)-1,3,8-TRIAZASPIRO[4.5]DEC-3-EN-2-ONE'>4QD</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=4zpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4zpf OCA], [https://pdbe.org/4zpf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4zpf RCSB], [https://www.ebi.ac.uk/pdbsum/4zpf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4zpf ProSAT]</span></td></tr> | |||
</table> | |||
== 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor. | |||
Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.,Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL Bioorg Med Chem Lett. 2015 Jun 29. pii: S0960-894X(15)00687-3. doi:, 10.1016/j.bmcl.2015.06.082. PMID:26195137<ref>PMID:26195137</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Orth | <div class="pdbe-citations 4zpf" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Orth P]] | |||
Latest revision as of 14:35, 6 November 2024
BACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-oneBACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one
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] Publication Abstract from PubMedThe IC50 of a beta-secretase (BACE-1) lead compound was improved approximately 200-fold from 11muM to 55nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor. Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.,Egbertson M, McGaughey GB, Pitzenberger SM, Stauffer SR, Coburn CA, Stachel SJ, Yang W, Barrow JC, Neilson LA, McWherter M, Perlow D, Fahr B, Munshi S, Allison TJ, Holloway K, Selnick HG, Yang Z, Swestock J, Simon AJ, Sankaranarayanan S, Colussi D, Tugusheva K, Lai MT, Pietrak B, Haugabook S, Jin L, Chen IW, Holahan M, Stranieri-Michener M, Cook JJ, Vacca J, Graham SL Bioorg Med Chem Lett. 2015 Jun 29. pii: S0960-894X(15)00687-3. doi:, 10.1016/j.bmcl.2015.06.082. PMID:26195137[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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