2va6

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|PDB= 2va6 |SIZE=350|CAPTION= <scene name='initialview01'>2va6</scene>, resolution 2.50&Aring;
|PDB= 2va6 |SIZE=350|CAPTION= <scene name='initialview01'>2va6</scene>, resolution 2.50&Aring;
|SITE= <scene name='pdbsite=AC2:Iod+Binding+Site+For+Chain+A'>AC2</scene>, <scene name='pdbsite=AC3:Iod+Binding+Site+For+Chain+A'>AC3</scene> and <scene name='pdbsite=AC4:H24+Binding+Site+For+Chain+A'>AC4</scene>
|SITE= <scene name='pdbsite=AC2:Iod+Binding+Site+For+Chain+A'>AC2</scene>, <scene name='pdbsite=AC3:Iod+Binding+Site+For+Chain+A'>AC3</scene> and <scene name='pdbsite=AC4:H24+Binding+Site+For+Chain+A'>AC4</scene>
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|LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene> and <scene name='pdbligand=H24:(6S)-2-amino-6-(3'-methoxybiphenyl-3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one'>H24</scene>
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|LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene> and <scene name='pdbligand=H24:(6S)-2-amino-6-(3&#39;-methoxybiphenyl-3-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one'>H24</scene>
|ACTIVITY= [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]
|ACTIVITY= [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]
|GENE=
|GENE=
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[[Category: zymogen]]
[[Category: zymogen]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:44:46 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 23 15:53:22 2008''

Revision as of 13:53, 23 March 2008

Image:2va6.jpg


PDB ID 2va6

Drag the structure with the mouse to rotate
, resolution 2.50Å
Sites: , and
Ligands: and
Activity: Memapsin 2, with EC number 3.4.23.46
Coordinates: save as pdb, mmCIF, xml



X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 24


Overview

Fragment-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.

About this Structure

2VA6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

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

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