4rrn: Difference between revisions
New page: '''Unreleased structure''' The entry 4rrn is ON HOLD Authors: Thomas, A.A, Hunt, K.W., Newhouse, B., Watts, R.J., Liu, X., Vigers, G.P.A., Smith, D., Rhodes, S.P., Brown, K.D., Otten, J... |
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==8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors== | |||
<StructureSection load='4rrn' size='340' side='right'caption='[[4rrn]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4rrn]] 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=4RRN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RRN 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=3UW:(4S,4AS,10AR)-2-AMINO-8-(2-FLUOROPYRIDIN-3-YL)-1-METHYL-3,4,4A,10A-TETRAHYDRO-2H-SPIRO[IMIDAZOLE-4,10-PYRANO[3,2-B]CHROMEN]-5(1H)-ONE'>3UW</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=4rrn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rrn OCA], [https://pdbe.org/4rrn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4rrn RCSB], [https://www.ebi.ac.uk/pdbsum/4rrn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4rrn 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 == | |||
A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Abeta1-40 at 60 mg/kg (PO). | |||
8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors.,Thomas AA, Hunt KW, Newhouse B, Watts RJ, Liu X, Vigers G, Smith D, Rhodes SP, Brown KD, Otten JN, Burkard M, Cox AA, Geck Do MK, Dutcher D, Rana S, DeLisle RK, Regal K, Wright AD, Groneberg R, Liao J, Scearce-Levie K, Siu M, Purkey HE, Lyssikatos JP J Med Chem. 2014 Nov 26. PMID:25411915<ref>PMID:25411915</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4rrn" 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: Brown KD]] | |||
[[Category: Burkard M]] | |||
[[Category: Cox AA]] | |||
[[Category: DeLisle RK]] | |||
[[Category: Dutcher D]] | |||
[[Category: Geck Do MK]] | |||
[[Category: Groneberg R]] | |||
[[Category: Hunt KW]] | |||
[[Category: Liao J]] | |||
[[Category: Liu X]] | |||
[[Category: Lyssikatos JP]] | |||
[[Category: Newhouse B]] | |||
[[Category: Otten JN]] | |||
[[Category: Purkey HE]] | |||
[[Category: Rana S]] | |||
[[Category: Regal K]] | |||
[[Category: Rhodes SP]] | |||
[[Category: Scearce-Levie K]] | |||
[[Category: Siu M]] | |||
[[Category: Smith D]] | |||
[[Category: Thomas AA]] | |||
[[Category: Vigers GPA]] | |||
[[Category: Watts RJ]] | |||
[[Category: Wright AD]] | |||