This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.


2fdp

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
(New page: 200px<br /> <applet load="2fdp" size="450" color="white" frame="true" align="right" spinBox="true" caption="2fdp, resolution 2.500&Aring;" /> '''Crystal structure ...)
Current revision (06:25, 3 April 2024) (edit) (undo)
 
(15 intermediate revisions not shown.)
Line 1: Line 1:
-
[[Image:2fdp.gif|left|200px]]<br />
 
-
<applet load="2fdp" size="450" color="white" frame="true" align="right" spinBox="true"
 
-
caption="2fdp, resolution 2.500&Aring;" />
 
-
'''Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor'''<br />
 
-
==Overview==
+
==Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor==
-
A series of novel beta-site amyloid precursor protein cleaving enzyme, (BACE-1) inhibitors containing an aminoethylene (AE) tetrahedral, intermediate isostere were synthesized and evaluated in comparison to, corresponding hydroxyethylene (HE) compounds. Enzymatic inhibitory values, were similar for both isosteres, as were structure-activity relationships, with respect to stereochemical preference and substituent variation, (P2/P3, P1, and P2'); however, the AE compounds were markedly more potent, in a cell-based assay for reduction of beta-secretase activity. The, incorporation of preferred P2/P3, P1, and P2' substituents into the AE, pharmacophore yielded compound 7, which possessed enzymatic and cell assay, IC(50)s of 26 nM and 180 nM, respectively. A three-dimensional crystal, structure of 7 in complex with BACE-1 revealed that the amino group of the, inhibitor core engages the catalytic aspartates in a manner analogous to, hydroxyl groups in HE inhibitors. The AE isostere class represents a, promising advance in the development of BACE-1 inhibitors.
+
<StructureSection load='2fdp' size='340' side='right'caption='[[2fdp]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 +
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[2fdp]] is a 3 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=2FDP OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2FDP 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]] 2.5&#8491;</td></tr>
 +
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FRP:N1-((2S,3S,5R)-3-AMINO-6-(4-FLUOROPHENYLAMINO)-5-METHYL-6-OXO-1-PHENYLHEXAN-2-YL)-N3,N3-DIPROPYLISOPHTHALAMIDE'>FRP</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=2fdp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2fdp OCA], [https://pdbe.org/2fdp PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2fdp RCSB], [https://www.ebi.ac.uk/pdbsum/2fdp PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2fdp 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>
 +
== Evolutionary Conservation ==
 +
[[Image:Consurf_key_small.gif|200px|right]]
 +
Check<jmol>
 +
<jmolCheckbox>
 +
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/fd/2fdp_consurf.spt"</scriptWhenChecked>
 +
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
 +
<text>to colour the structure by Evolutionary Conservation</text>
 +
</jmolCheckbox>
 +
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2fdp ConSurf].
 +
<div style="clear:both"></div>
-
==About this Structure==
+
==See Also==
-
2FDP 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 FRP as [http://en.wikipedia.org/wiki/ligand ligand]. 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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2FDP OCA].
+
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
-
 
+
== References ==
-
==Reference==
+
<references/>
-
Aminoethylenes: a tetrahedral intermediate isostere yielding potent inhibitors of the aspartyl protease BACE-1., Yang W, Lu W, Lu Y, Zhong M, Sun J, Thomas AE, Wilkinson JM, Fucini RV, Lam M, Randal M, Shi XP, Jacobs JW, McDowell RS, Gordon EM, Ballinger MD, J Med Chem. 2006 Feb 9;49(3):839-42. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16451048 16451048]
+
__TOC__
 +
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
-
[[Category: Memapsin 2]]
+
[[Category: Large Structures]]
-
[[Category: Single protein]]
+
[[Category: Ballinger MD]]
-
[[Category: Ballinger, M.D.]]
+
[[Category: Fucini RV]]
-
[[Category: Fucini, R.V.]]
+
[[Category: Gordon EM]]
-
[[Category: Gordon, E.M.]]
+
[[Category: Jacobs JW]]
-
[[Category: Jacobs, J.W.]]
+
[[Category: Lam M]]
-
[[Category: Lam, M.]]
+
[[Category: Lu W]]
-
[[Category: Lu, W.]]
+
[[Category: Lu Y]]
-
[[Category: Lu, Y.]]
+
[[Category: McDowell RS]]
-
[[Category: McDowell, R.S.]]
+
[[Category: Randal M]]
-
[[Category: Randal, M.]]
+
[[Category: Shi XP]]
-
[[Category: Shi, X.P.]]
+
[[Category: Sun J]]
-
[[Category: Sun, J.]]
+
[[Category: Thomas AE]]
-
[[Category: Thomas, A.E.]]
+
[[Category: Wilkinson JM]]
-
[[Category: Wilkinson, J.M.]]
+
[[Category: Yang W]]
-
[[Category: Yang, W.]]
+
[[Category: Zhong M]]
-
[[Category: Zhong, M.]]
+
-
[[Category: FRP]]
+
-
[[Category: aspartyl protease]]
+
-
[[Category: bace]]
+
-
 
+
-
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:03:43 2007''
+

Current revision

Crystal structure of beta-secretase complexed with an amino-ethylene inhibitor

PDB ID 2fdp

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2fdp"
Personal tools