6nv9: Difference between revisions
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<StructureSection load='6nv9' size='340' side='right'caption='[[6nv9]], [[Resolution|resolution]] 2.13Å' scene=''> | <StructureSection load='6nv9' size='340' side='right'caption='[[6nv9]], [[Resolution|resolution]] 2.13Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6nv9]] is a 3 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6nv9]] is a 3 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=6NV9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NV9 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=L3M:(3S)-3-hydroxy-N-(2-methylpropyl)-N~2~-{[(4S)-17-[(methylsulfonyl)(propyl)amino]-2-oxo-3-azatricyclo[13.3.1.1~6,10~]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}-L-norleucinamide'>L3M</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.13Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=L3M:(3S)-3-hydroxy-N-(2-methylpropyl)-N~2~-{[(4S)-17-[(methylsulfonyl)(propyl)amino]-2-oxo-3-azatricyclo[13.3.1.1~6,10~]icosa-1(19),6(20),7,9,15,17-hexaen-4-yl]methyl}-L-norleucinamide'>L3M</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6nv9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6nv9 OCA], [https://pdbe.org/6nv9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6nv9 RCSB], [https://www.ebi.ac.uk/pdbsum/6nv9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6nv9 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</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> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 6nv9" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6nv9" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Ghosh AK]] | |||
[[Category: Ghosh | [[Category: Mesecar AD]] | ||
[[Category: Mesecar | [[Category: Yen YC]] | ||
[[Category: Yen | |||
Latest revision as of 10:00, 11 October 2023
BACE1 in complex with a macrocyclic inhibitorBACE1 in complex with a macrocyclic inhibitor
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 PubMedBACE1 (Beta-site Amyloid precursor protein (APP) Cleaving Enzyme 1) is a promising therapeutic target for Alzheimer's disease (AD). However, efficient expression, purification and crystallization systems are not well described or detailed in the literature nor are approaches for treatment of enzyme kinetic data for potent inhibitors well described. We therefore developed a platform for expression and purification of BACE1, including protein refolding from inclusion bodies, from E.coli in addition to optimizing a reproducible crystallization procedure of BACE1 bound with inhibitors. We also report a detailed approach to the proper analysis of enzyme kinetic data for compounds that exhibit either rapid-equilibrium or tight-binding mechanisms. Our methods allow for the purification of ~15 mg of BACE1 enzyme from 1 L of culture which is higher than reported yields in the current literature. To evaluate the data analysis approach developed here, a well-known potent inhibitor and two of its derivatives were tested, analyzed and compared. The inhibitory constants (Ki) obtained from the kinetic studies are in agreement with dissociation constants (Kd) that were also determined using isothermal titration calorimetry (ITC) experiments. The X-ray structures of these three compounds in complex with BACE1 were readily obtained and provide important insight into the structure and thermodynamics of the BACE1-inhibitor interactions. Development of an efficient enzyme production and structure-based discovery platform for BACE1 inhibitors.,Yen YC, Kammeyer A, Jensen KC, Tirlangi J, Ghosh AK, Mesecar AD Biochemistry. 2019 Sep 24. doi: 10.1021/acs.biochem.9b00714. PMID:31549827[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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