6c2i

From Proteopedia

(Difference between revisions)

Revision as of 08:04, 21 March 2018

Structure of Bace-1 (Beta-Secretase) in complex with : N-(3-((1R,5S,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

Structural highlights

6c2i 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

The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Abeta40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease.

Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation.,Low JD, Bartberger MD, Cheng Y, Whittington D, Xue Q, Wood S, Allen JR, Minatti AE Bioorg Med Chem Lett. 2018 Feb 1. pii: S0960-894X(18)30067-2. doi:, 10.1016/j.bmcl.2018.01.056. PMID:29426770^[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
↑ Low JD, Bartberger MD, Cheng Y, Whittington D, Xue Q, Wood S, Allen JR, Minatti AE. Diastereoselective synthesis of fused cyclopropyl-3-amino-2,4-oxazine beta-amyloid cleaving enzyme (BACE) inhibitors and their biological evaluation. Bioorg Med Chem Lett. 2018 Feb 1. pii: S0960-894X(18)30067-2. doi:, 10.1016/j.bmcl.2018.01.056. PMID:29426770 doi:http://dx.doi.org/10.1016/j.bmcl.2018.01.056

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6c2i"

@@ Line 3: / Line 3: @@
 <StructureSection load='6c2i' size='340' side='right' caption='[[6c2i]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6c2i]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6C2I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C2I FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6c2i]] 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=6C2I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6C2I FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EJ7:N-{3-[(1R,5S,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl]-4-fluorophenyl}-5-methoxypyrazine-2-carboxamide'>EJ7</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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 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=6c2i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6c2i OCA], [http://pdbe.org/6c2i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6c2i RCSB], [http://www.ebi.ac.uk/pdbsum/6c2i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6c2i ProSAT]</span></td></tr>
@@ Line 23: / Line 24: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Memapsin 2]]
 [[Category: Sickmier, E A]]

6c2i

From Proteopedia

Revision as of 08:04, 21 March 2018

Structure of Bace-1 (Beta-Secretase) in complex with : N-(3-((1R,5S,6R)-3-amino-5-methyl-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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