6eqm: Difference between revisions
New page: '''Unreleased structure''' The entry 6eqm is ON HOLD until Paper Publication Authors: Rondeau, J.M., Wirth, E. Description: Crystal Structure of Human BACE-1 in Complex with CNP520 [[C... |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Crystal Structure of Human BACE-1 in Complex with CNP520== | |||
<StructureSection load='6eqm' size='340' side='right'caption='[[6eqm]], [[Resolution|resolution]] 1.35Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6eqm]] 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=6EQM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EQM 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]] 1.35Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BUH:~{N}-[6-[(3~{R},6~{R})-5-azanyl-3,6-dimethyl-6-(trifluoromethyl)-2~{H}-1,4-oxazin-3-yl]-5-fluoranyl-pyridin-2-yl]-3-chloranyl-5-(trifluoromethyl)pyridine-2-carboxamide'>BUH</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=6eqm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6eqm OCA], [https://pdbe.org/6eqm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6eqm RCSB], [https://www.ebi.ac.uk/pdbsum/6eqm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6eqm 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 beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-beta (Abeta), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Abeta therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Abeta in rats and dogs, and Abeta plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults >/= 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Abeta reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program. | |||
The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.,Neumann U, Ufer M, Jacobson LH, Rouzade-Dominguez ML, Huledal G, Kolly C, Luond RM, Machauer R, Veenstra SJ, Hurth K, Rueeger H, Tintelnot-Blomley M, Staufenbiel M, Shimshek DR, Perrot L, Frieauff W, Dubost V, Schiller H, Vogg B, Beltz K, Avrameas A, Kretz S, Pezous N, Rondeau JM, Beckmann N, Hartmann A, Vormfelde S, David OJ, Galli B, Ramos R, Graf A, Lopez Lopez C EMBO Mol Med. 2018 Sep 17. pii: emmm.201809316. doi: 10.15252/emmm.201809316. PMID:30224383<ref>PMID:30224383</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6eqm" style="background-color:#fffaf0;"></div> | ||
[[Category: Rondeau | |||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Rondeau J-M]] | |||
[[Category: Wirth E]] | |||
Latest revision as of 10:55, 17 October 2024
Crystal Structure of Human BACE-1 in Complex with CNP520Crystal Structure of Human BACE-1 in Complex with CNP520
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 beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-beta (Abeta), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Abeta therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Abeta in rats and dogs, and Abeta plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults >/= 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Abeta reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.,Neumann U, Ufer M, Jacobson LH, Rouzade-Dominguez ML, Huledal G, Kolly C, Luond RM, Machauer R, Veenstra SJ, Hurth K, Rueeger H, Tintelnot-Blomley M, Staufenbiel M, Shimshek DR, Perrot L, Frieauff W, Dubost V, Schiller H, Vogg B, Beltz K, Avrameas A, Kretz S, Pezous N, Rondeau JM, Beckmann N, Hartmann A, Vormfelde S, David OJ, Galli B, Ramos R, Graf A, Lopez Lopez C EMBO Mol Med. 2018 Sep 17. pii: emmm.201809316. doi: 10.15252/emmm.201809316. PMID:30224383[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||