4dh6

From Proteopedia

(Difference between revisions)

Revision as of 13:45, 4 August 2016

Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide

Structural highlights

4dh6 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Gene:	BACE1, BACE, KIAA1149 (HUMAN)
Activity:	Memapsin 2, with EC number 3.4.23.46
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1] ^[2]

Publication Abstract from PubMed

A series of potent hydroxyethyl amine (HEA) derived inhibitors of ss-site APP cleaving enzyme (BACE) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogs that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS ss-amyloid (Ass) in Sprague Dawley rats following oral administration.

Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central ss-amyloid.,Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dineen TA, Esmay J, Graceffa RF, Harried S, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, Rattan C, San Miguel T, Sickmier EA, Wahl RC, Wen PH, Wood S, Xue Q, Yang BH, Patel VF, Zhong W J Med Chem. 2012 Apr 2. PMID:22468639^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Weiss MM, Williamson T, Babu-Khan S, Bartberger MD, Brown J, Chen K, Cheng Y, Citron M, Croghan MD, Dineen TA, Esmay J, Graceffa RF, Harried S, Hickman D, Hitchcock SA, Horne DB, Huang H, Imbeah-Ampiah R, Judd T, Kaller MR, Kreiman CR, La DS, Li V, Lopez P, Louie S, Monenschein H, Nguyen TT, Pennington LD, Rattan C, San Miguel T, Sickmier EA, Wahl RC, Wen PH, Wood S, Xue Q, Yang BH, Patel VF, Zhong W. Design and preparation of a potent series of hydroxyethylamine containing beta-secretase inhibitors that demonstrate robust reduction of central ss-amyloid. J Med Chem. 2012 Apr 2. PMID:22468639 doi:10.1021/jm300119p

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4dh6"

@@ Line 1: / Line 1: @@
 ==Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide==
 <StructureSection load='4dh6' size='340' side='right' caption='[[4dh6]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4dh6]] is a 1 chain structure with 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=4DH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DH6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4dh6]] 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=4DH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DH6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0KN:(2R)-N-[(2S,3R)-1-(1,3-BENZODIOXOL-5-YL)-4-{[(4S)-6-(2,2-DIMETHYLPROPYL)-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL]AMINO}-3-HYDROXYBUTAN-2-YL]-2-METHOXYPROPANAMIDE'>0KN</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dh6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dh6 RCSB], [http://www.ebi.ac.uk/pdbsum/4dh6 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dh6 OCA], [http://pdbe.org/4dh6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4dh6 RCSB], [http://www.ebi.ac.uk/pdbsum/4dh6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4dh6 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4dh6" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 25: / Line 27: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Memapsin 2]]
 [[Category: Sickmier, E A]]

4dh6

From Proteopedia

Revision as of 13:45, 4 August 2016

Structure of Bace-1 (Beta-Secretase) in Complex with (2R)-N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4-((S)-6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridine]-4'-ylamino)butan-2-yl)-2-methoxypropanamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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