2va5: Difference between revisions

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Revision as of 19:44, 20 March 2008

File:2va5.jpg

, resolution 2.75Å

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 8C

OverviewOverview

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 StructureAbout this Structure

2VA5 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

ReferenceReference

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

Page seeded by OCA on Thu Mar 20 18:44:47 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
-[[Image:2va5.jpg|left|200px]]<br /><applet load="2va5" size="350" color="white" frame="true" align="right" spinBox="true"
+[[Image:2va5.jpg|left|200px]]
-caption="2va5, resolution 2.75&Aring;" />
-'''X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C'''<br />
+ {{Structure
+|PDB= 2va5 |SIZE=350|CAPTION= <scene name='initialview01'>2va5</scene>, resolution 2.75&Aring;
+|SITE= <scene name='pdbsite=AC1:Iod+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC3:C8c+Binding+Site+For+Chain+A'>AC3</scene>
+|LIGAND= <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene> and <scene name='pdbligand=C8C:2-amino-6-[2-(1H-indol-6-yl)ethyl]pyrimidin-4(3H)-one'>C8C</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]
+|GENE=
+}}
+'''X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C'''
 ==Overview==
@@ Line 7: / Line 16: @@
 ==About this Structure==
-VA5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=IOD:'>IOD</scene> and <scene name='pdbligand=C8C:'>C8C</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Known structural/functional Sites: <scene name='pdbsite=AC1:Iod+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC3:C8c+Binding+Site+For+Chain+A'>AC3</scene>. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VA5 OCA].
+VA5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VA5 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:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17985862 17985862]
+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:[http://www.ncbi.nlm.nih.gov/pubmed/17985862 17985862]
 [[Category: Homo sapiens]]
 [[Category: Memapsin 2]]
@@ Line 52: / Line 61: @@
 [[Category: zymogen]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:54:31 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:44:47 2008''