2va5: Difference between revisions
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==X-ray crystal structure of beta secretase complexed with compound 8c== | ==X-ray crystal structure of beta secretase complexed with compound 8c== | ||
<StructureSection load='2va5' size='340' side='right' caption='[[2va5]], [[Resolution|resolution]] 2.75Å' scene=''> | <StructureSection load='2va5' size='340' side='right'caption='[[2va5]], [[Resolution|resolution]] 2.75Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[2va5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VA5 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[2va5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VA5 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2VA5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C8C:2-AMINO-6-[2-(1H-INDOL-6-YL)ETHYL]PYRIMIDIN-4(3H)-ONE'>C8C</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C8C:2-AMINO-6-[2-(1H-INDOL-6-YL)ETHYL]PYRIMIDIN-4(3H)-ONE'>C8C</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1m4h|1m4h]], [[1sgz|1sgz]], [[1w50|1w50]], [[1w51|1w51]], [[1xs7|1xs7]], [[1ym4|1ym4]], [[1fkn|1fkn]], [[1py1|1py1]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1ym2|1ym2]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2va6|2va6]], [[2va7|2va7]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1m4h|1m4h]], [[1sgz|1sgz]], [[1w50|1w50]], [[1w51|1w51]], [[1xs7|1xs7]], [[1ym4|1ym4]], [[1fkn|1fkn]], [[1py1|1py1]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1ym2|1ym2]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2va6|2va6]], [[2va7|2va7]]</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2va5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2va5 OCA], [http://pdbe.org/2va5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2va5 RCSB], [http://www.ebi.ac.uk/pdbsum/2va5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2va5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
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==See Also== | ==See Also== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Human]] | [[Category: Human]] | ||
[[Category: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Aharony, D]] | [[Category: Aharony, D]] | ||
Revision as of 14:24, 17 June 2020
X-ray crystal structure of beta secretase complexed with compound 8cX-ray crystal structure of beta secretase complexed with compound 8c
Structural highlights
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 PubMedFragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization. Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.,Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell JB, Carr RA, Chessari G, Congreve M, Frederickson M, Folmer RH, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson LL, Patel S, Spear N, Tian G J Med Chem. 2007 Nov 29;50(24):5912-25. Epub 2007 Nov 7. PMID:17985862[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Human
- Large Structures
- Memapsin 2
- Aharony, D
- Albert, J S
- Andisik, D
- Callaghan, O
- Campbell, J B
- Carr, R A
- Chessari, G
- Congreve, M
- Edwards, P D
- Folmer, R H.A
- Frederickson, M
- Geschwindner, S
- Koether, G
- Kolmodin, K
- Krumrine, J
- Mauger, R C
- Murray, C W
- Olsson, L
- Patel, S
- Spear, N
- Sylvester, M
- Tian, G
- Alternative splicing
- Alzheimer's disease
- Aspartic protease
- Aspartyl protease
- Base
- Beta-secretase
- Glycoprotein
- Hydrolase
- Membrane
- Protease
- Transmembrane
- Zymogen