4wtu

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22

Structural highlights

4wtu is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	, ,
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

BACE1 inhibition to prevent Abeta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Abeta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

An Orally Available BACE1 Inhibitor That Affords Robust CNS Abeta Reduction without Cardiovascular Liabilities.,Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn RT 2nd, Epstein O, Fremeau RT Jr, Harried S, Hickman D, Hitchcock SA, Luo Y, Minatti AE, Patel VF, Vargas HM, Wahl RC, Weiss MM, Wen PH, White RD, Whittington DA, Zheng XM, Wood S ACS Med Chem Lett. 2014 Dec 29;6(2):210-5. doi: 10.1021/ml500458t. eCollection, 2015 Feb 12. PMID:25699151^[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
↑ Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn RT 2nd, Epstein O, Fremeau RT Jr, Harried S, Hickman D, Hitchcock SA, Luo Y, Minatti AE, Patel VF, Vargas HM, Wahl RC, Weiss MM, Wen PH, White RD, Whittington DA, Zheng XM, Wood S. An Orally Available BACE1 Inhibitor That Affords Robust CNS Abeta Reduction without Cardiovascular Liabilities. ACS Med Chem Lett. 2014 Dec 29;6(2):210-5. doi: 10.1021/ml500458t. eCollection, 2015 Feb 12. PMID:25699151 doi:http://dx.doi.org/10.1021/ml500458t

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/4wtu"

Categories: Homo sapiens | Large Structures | Long AM | Whittington DA

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 4wtu is ON HOLD  until Paper Publication
+==Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22==
+<StructureSection load='4wtu' size='340' side='right'caption='[[4wtu]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4wtu]] is a 1 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=4WTU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WTU 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]] 1.85&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3UT:(5S)-3-(5,6-DIHYDRO-2H-PYRAN-3-YL)-1-FLUORO-7-(2-FLUOROPYRIDIN-3-YL)SPIRO[CHROMENO[2,3-C]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3UT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=4wtu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wtu OCA], [https://pdbe.org/4wtu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wtu RCSB], [https://www.ebi.ac.uk/pdbsum/4wtu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wtu 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+BACE1 inhibition to prevent Abeta peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Abeta levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.
-Authors: Whittington, D.A., Long, A.M.
+An Orally Available BACE1 Inhibitor That Affords Robust CNS Abeta Reduction without Cardiovascular Liabilities.,Cheng Y, Brown J, Judd TC, Lopez P, Qian W, Powers TS, Chen JJ, Bartberger MD, Chen K, Dunn RT 2nd, Epstein O, Fremeau RT Jr, Harried S, Hickman D, Hitchcock SA, Luo Y, Minatti AE, Patel VF, Vargas HM, Wahl RC, Weiss MM, Wen PH, White RD, Whittington DA, Zheng XM, Wood S ACS Med Chem Lett. 2014 Dec 29;6(2):210-5. doi: 10.1021/ml500458t. eCollection, 2015 Feb 12. PMID:25699151<ref>PMID:25699151</ref>
-Description: Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4wtu" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Long AM]]
+[[Category: Whittington DA]]

4wtu

From Proteopedia

Current revision

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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