4xkx

From Proteopedia

(Difference between revisions)

Revision as of 15:46, 7 February 2015

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28

Structural highlights

4xkx is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4wtu, 4rcd, 4rce, 4rcf
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

The beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Abeta levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious beta-secretase inhibitors for the potential treatment of Alzheimer's disease.,Chen JJ, Liu Q, Yuan C, Gore V, Lopez P, Ma V, Amegadzie A, Qian W, Judd TC, Minatti AE, Brown J, Cheng Y, Xue M, Zhong W, Dineen TA, Epstein O, Human J, Kreiman C, Marx I, Weiss MM, Hitchcock SA, Powers TS, Chen K, Wen PH, Whittington DA, Cheng AC, Bartberger MD, Hickman D, Werner JA, Vargas HM, Everds NE, Vonderfecht SL, Dunn RT 2nd, Wood S, Fremeau RT Jr, White RD, Patel VF Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. , Epub 2015 Jan 8. PMID:25613679^[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
↑ Chen JJ, Liu Q, Yuan C, Gore V, Lopez P, Ma V, Amegadzie A, Qian W, Judd TC, Minatti AE, Brown J, Cheng Y, Xue M, Zhong W, Dineen TA, Epstein O, Human J, Kreiman C, Marx I, Weiss MM, Hitchcock SA, Powers TS, Chen K, Wen PH, Whittington DA, Cheng AC, Bartberger MD, Hickman D, Werner JA, Vargas HM, Everds NE, Vonderfecht SL, Dunn RT 2nd, Wood S, Fremeau RT Jr, White RD, Patel VF. Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious beta-secretase inhibitors for the potential treatment of Alzheimer's disease. Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. , Epub 2015 Jan 8. PMID:25613679 doi:http://dx.doi.org/10.1016/j.bmcl.2014.12.092

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/4xkx"

Categories: Memapsin 2 | Long, A M | Whittington, D A | Aspartic protease | Hydrolase-hydrolase inhibitor complex

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28==
+<StructureSection load='4xkx' size='340' side='right' caption='[[4xkx]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4xkx]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4XKX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XKX FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=43K:(5S)-7-(2-FLUOROPYRIDIN-3-YL)-3-(2-FLUOROPYRIDIN-4-YL)SPIRO[CHROMENO[2,3-C]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>43K</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4wtu|4wtu]], [[4rcd|4rcd]], [[4rce|4rce]], [[4rcf|4rcf]]</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=4xkx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xkx OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4xkx RCSB], [http://www.ebi.ac.uk/pdbsum/4xkx PDBsum]</span></td></tr>
+</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 ==
+The beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Abeta levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.
-The entry 4xkx is ON HOLD
+Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious beta-secretase inhibitors for the potential treatment of Alzheimer's disease.,Chen JJ, Liu Q, Yuan C, Gore V, Lopez P, Ma V, Amegadzie A, Qian W, Judd TC, Minatti AE, Brown J, Cheng Y, Xue M, Zhong W, Dineen TA, Epstein O, Human J, Kreiman C, Marx I, Weiss MM, Hitchcock SA, Powers TS, Chen K, Wen PH, Whittington DA, Cheng AC, Bartberger MD, Hickman D, Werner JA, Vargas HM, Everds NE, Vonderfecht SL, Dunn RT 2nd, Wood S, Fremeau RT Jr, White RD, Patel VF Bioorg Med Chem Lett. 2015 Feb 15;25(4):767-74. doi: 10.1016/j.bmcl.2014.12.092. , Epub 2015 Jan 8. PMID:25613679<ref>PMID:25613679</ref>
-Authors: Whittington, D.A., Long, A.M.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Whittington, D.A]]
+__TOC__
-[[Category: Long, A.M]]
+</StructureSection>
+[[Category: Memapsin 2]]
+[[Category: Long, A M]]
+[[Category: Whittington, D A]]
+[[Category: Aspartic protease]]
+[[Category: Hydrolase-hydrolase inhibitor complex]]

4xkx

From Proteopedia

Revision as of 15:46, 7 February 2015

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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