2v00
From Proteopedia
(New page: 200px<br /><applet load="2v00" size="350" color="white" frame="true" align="right" spinBox="true" caption="2v00, resolution 1.55Å" /> '''X-RAY CRYSTAL STRUCT...) |
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==Overview== | ==Overview== | ||
| - | Fragment-based lead generation was applied to find novel small-molecule | + | Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1. |
==About this Structure== | ==About this Structure== | ||
| - | 2V00 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=V15:'>V15</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] Known structural/functional Sites: <scene name='pdbsite=AC1:Gol Binding Site For Chain A'>AC1</scene>, <scene name='pdbsite=AC2:Gol Binding Site For Chain A'>AC2</scene>, <scene name='pdbsite=AC3:Gol Binding Site For Chain A'>AC3</scene>, <scene name='pdbsite=AC4:Act Binding Site For Chain A'>AC4</scene>, <scene name='pdbsite=AC5:Act Binding Site For Chain A'>AC5</scene> and <scene name='pdbsite=AC6:V15 Binding Site For Chain A'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V00 OCA]. | + | 2V00 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Cryphonectria_parasitica Cryphonectria parasitica] with <scene name='pdbligand=ACT:'>ACT</scene>, <scene name='pdbligand=V15:'>V15</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Endothiapepsin Endothiapepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.22 3.4.23.22] Known structural/functional Sites: <scene name='pdbsite=AC1:Gol+Binding+Site+For+Chain+A'>AC1</scene>, <scene name='pdbsite=AC2:Gol+Binding+Site+For+Chain+A'>AC2</scene>, <scene name='pdbsite=AC3:Gol+Binding+Site+For+Chain+A'>AC3</scene>, <scene name='pdbsite=AC4:Act+Binding+Site+For+Chain+A'>AC4</scene>, <scene name='pdbsite=AC5:Act+Binding+Site+For+Chain+A'>AC5</scene> and <scene name='pdbsite=AC6:V15+Binding+Site+For+Chain+A'>AC6</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2V00 OCA]. |
==Reference== | ==Reference== | ||
| - | Discovery of a | + | Discovery of a novel warhead against beta-secretase through fragment-based lead generation., Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, de Beer T, Folmer RH, J Med Chem. 2007 Nov 29;50(24):5903-11. Epub 2007 Nov 7. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17985861 17985861] |
[[Category: Cryphonectria parasitica]] | [[Category: Cryphonectria parasitica]] | ||
[[Category: Endothiapepsin]] | [[Category: Endothiapepsin]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Albert, J | + | [[Category: Albert, J S.]] |
| - | [[Category: Beer, T | + | [[Category: Beer, T De.]] |
[[Category: Deinum, J.]] | [[Category: Deinum, J.]] | ||
| - | [[Category: Edwards, P | + | [[Category: Edwards, P D.]] |
| - | [[Category: Folmer, R | + | [[Category: Folmer, R H.A.]] |
[[Category: Geschwindner, S.]] | [[Category: Geschwindner, S.]] | ||
| - | [[Category: Olsson, L | + | [[Category: Olsson, L L.]] |
[[Category: ACT]] | [[Category: ACT]] | ||
[[Category: GOL]] | [[Category: GOL]] | ||
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[[Category: zymogen]] | [[Category: zymogen]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:51:59 2008'' |
Revision as of 16:52, 21 February 2008
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X-RAY CRYSTAL STRUCTURE OF ENDOTHIAPEPSIN COMPLEXED WITH COMPOUND 1
Overview
Fragment-based lead generation was applied to find novel small-molecule inhibitors of beta-secretase (BACE-1), a key target for the treatment of Alzheimer's disease. Fragment hits coming from a 1D NMR screen were characterized by BIAcore, and the most promising compounds were soaked into protein crystals to help the rational design of more potent hit analogues. Problems arising due to our inability to grow BACE-1 crystals at the biologically relevant pH at which the screen was run were overcome by using endothiapepsin as a surrogate aspartyl protease. Among others, we identified 6-substituted isocytosines as a novel warhead against BACE-1, and the accompanying paper in this journal describes how these were optimized to a lead series of nanomolar inhibitors.1.
About this Structure
2V00 is a Single protein structure of sequence from Cryphonectria parasitica with , and as ligands. Active as Endothiapepsin, with EC number 3.4.23.22 Known structural/functional Sites: , , , , and . Full crystallographic information is available from OCA.
Reference
Discovery of a novel warhead against beta-secretase through fragment-based lead generation., Geschwindner S, Olsson LL, Albert JS, Deinum J, Edwards PD, de Beer T, Folmer RH, J Med Chem. 2007 Nov 29;50(24):5903-11. Epub 2007 Nov 7. PMID:17985861
Page seeded by OCA on Thu Feb 21 18:51:59 2008
Categories: Cryphonectria parasitica | Endothiapepsin | Single protein | Albert, J S. | Beer, T De. | Deinum, J. | Edwards, P D. | Folmer, R H.A. | Geschwindner, S. | Olsson, L L. | ACT | GOL | V15 | Alzheimer's disease | Aspartyl protease | B- secretase | Bace | Fragment hit | Fragment-based lead generation | Hydrolase | Isocytosine | Protease | Surrogate protein | Zymogen
