6fgy: Difference between revisions

Latest revision as of 07:57, 17 October 2024

Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4

Structural highlights

6fgy 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 1.54Å
Ligands:	D9W
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

New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Abeta levels in mice in an acute treatment regimen.

Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.,Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741^[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
↑ Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741 doi:https://dx.doi.org/10.1016/j.bmcl.2018.05.003

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R. Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors. Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741 doi:https://dx.doi.org/10.1016/j.bmcl.2018.05.003

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6fgy is ON HOLD
+==Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4==
+<StructureSection load='6fgy' size='340' side='right'caption='[[6fgy]], [[Resolution|resolution]] 1.54&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6fgy]] 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=6FGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FGY 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]] 1.54&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D9W:~{N}-[3-[(3~{R})-5-azanyl-3-methyl-2,6-dihydro-1,4-oxazin-3-yl]phenyl]-5-bromanyl-pyridine-2-carboxamide'>D9W</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=6fgy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6fgy OCA], [https://pdbe.org/6fgy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6fgy RCSB], [https://www.ebi.ac.uk/pdbsum/6fgy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6fgy 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 ==
+New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Abeta levels in mice in an acute treatment regimen.
-Authors: Rondeau, J.M., Bourgier, E.
+Discovery of amino-1,4-oxazines as potent BACE-1 inhibitors.,Veenstra SJ, Rueeger H, Voegtle M, Lueoend R, Holzer P, Hurth K, Tintelnot-Blomley M, Frederiksen M, Rondeau JM, Jacobson L, Staufenbiel M, Neumann U, Machauer R Bioorg Med Chem Lett. 2018 May 3. pii: S0960-894X(18)30393-7. doi:, 10.1016/j.bmcl.2018.05.003. PMID:29764741<ref>PMID:29764741</ref>
-Description: Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Rondeau, J.M]]
+<div class="pdbe-citations 6fgy" style="background-color:#fffaf0;"></div>
-[[Category: Bourgier, E]]
+==See Also==
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bourgier E]]
+[[Category: Rondeau J-M]]

6fgy: Difference between revisions

Latest revision as of 07:57, 17 October 2024

Crystal Structure of Human BACE-1 in Complex with amino-1,4-oxazine compound 4

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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