4dus

From Proteopedia

(Difference between revisions)

Revision as of 15:19, 25 December 2014

Structure of Bace-1 (Beta-Secretase) in complex with N-((2S,3R)-1-(4-fluorophenyl)-3-hydroxy-4-((6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)butan-2-yl)acetamide

Structural highlights

4dus 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:	, ,
Related:	3rsv
Gene:	BACE1, BACE, KIAA1149 (HUMAN)
Activity:	Memapsin 2, with EC number 3.4.23.46
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

beta-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against beta-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Abeta40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.

A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of beta-Secretase.,Kaller MR, Harried SS, Albrecht B, Amarante P, Babu-Khan S, Bartberger MD, Brown J, Brown R, Chen K, Cheng Y, Citron M, Croghan MD, Graceffa R, Hickman D, Judd T, Kriemen C, La D, Li V, Lopez P, Luo Y, Masse C, Monenschein H, Nguyen T, Pennington LD, Miguel TS, Sickmier EA, Wahl RC, Weiss MM, Wen PH, Williamson T, Wood S, Xue M, Yang B, Zhang J, Patel V, Zhong W, Hitchcock S ACS Med Chem Lett. 2012 Mar 29;3(11):886-91. doi: 10.1021/ml3000148. eCollection , 2012 Nov 8. PMID:24900403^[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
↑ Kaller MR, Harried SS, Albrecht B, Amarante P, Babu-Khan S, Bartberger MD, Brown J, Brown R, Chen K, Cheng Y, Citron M, Croghan MD, Graceffa R, Hickman D, Judd T, Kriemen C, La D, Li V, Lopez P, Luo Y, Masse C, Monenschein H, Nguyen T, Pennington LD, Miguel TS, Sickmier EA, Wahl RC, Weiss MM, Wen PH, Williamson T, Wood S, Xue M, Yang B, Zhang J, Patel V, Zhong W, Hitchcock S. A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of beta-Secretase. ACS Med Chem Lett. 2012 Mar 29;3(11):886-91. doi: 10.1021/ml3000148. eCollection , 2012 Nov 8. PMID:24900403 doi:http://dx.doi.org/10.1021/ml3000148

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/4dus"

@@ Line 3: / Line 3: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4dus]] 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=4DUS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DUS FirstGlance]. <br>
-</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MP:N-((2S,3R)-1-(4-FLUOROPHENYL)-3-HYDROXY-4-((6-NEOPENTYL-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL)AMINO)BUTAN-2-YL)ACETAMIDE'>0MP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene><br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MP:N-((2S,3R)-1-(4-FLUOROPHENYL)-3-HYDROXY-4-((6-NEOPENTYL-3,4-DIHYDROSPIRO[CYCLOBUTANE-1,2-PYRANO[2,3-B]PYRIDIN]-4-YL)AMINO)BUTAN-2-YL)ACETAMIDE'>0MP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
-<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rsv|3rsv]]</td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3rsv|3rsv]]</td></tr>
-<tr><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='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><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='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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4dus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dus OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dus RCSB], [http://www.ebi.ac.uk/pdbsum/4dus 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=4dus FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dus OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4dus RCSB], [http://www.ebi.ac.uk/pdbsum/4dus PDBsum]</span></td></tr>
-<table>
+</table>
+== Function ==
+[[http://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>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 28: @@
 [[Category: Human]]
 [[Category: Memapsin 2]]
-[[Category: Sickmier, E A.]]
+[[Category: Sickmier, E A]]
 [[Category: App]]
 [[Category: Aspartyl protease]]
 [[Category: Hydrolase]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]

4dus

From Proteopedia

Revision as of 15:19, 25 December 2014

Structure of Bace-1 (Beta-Secretase) in complex with N-((2S,3R)-1-(4-fluorophenyl)-3-hydroxy-4-((6'-neopentyl-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl)amino)butan-2-yl)acetamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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