4lxa: Difference between revisions

Revision as of 12:18, 5 August 2016

Crystal Structure of Human Beta Secretase in Complex with Compound 11a

Structural highlights

4lxa is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	1YS, GOL, PO4
Related:	4lxk, 4lxm
Gene:	BACE, BACE1, 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

Previous structure based optimization in our laboratories led to the identification of a novel, high-affinity cyclic sulfone hydroxyethylamine-derived inhibitor such as 1 that lowers CNS-derived Abeta following oral administration to transgenic APP51/16 mice. Herein we report SAR development in the S3 and S2' subsites of BACE1 for cyclic sulfoxide hydroxyethyl amine inhibitors, the synthetic approaches employed in this effort, and in vivo data for optimized compound such as 11d.

Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides.,Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H, Neumann U Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6. doi: 10.1016/j.bmcl.2013.07.071. , Epub 2013 Aug 9. PMID:23981898^[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
↑ Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H, Neumann U. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6. doi: 10.1016/j.bmcl.2013.07.071. , Epub 2013 Aug 9. PMID:23981898 doi:https://dx.doi.org/10.1016/j.bmcl.2013.07.071

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] Rueeger H, Lueoend R, Machauer R, Veenstra SJ, Jacobson LH, Staufenbiel M, Desrayaud S, Rondeau JM, Mobitz H, Neumann U. Discovery of cyclic sulfoxide hydroxyethylamines as potent and selective beta-site APP-cleaving enzyme 1 (BACE1) inhibitors: structure based design and in vivo reduction of amyloid beta-peptides. Bioorg Med Chem Lett. 2013 Oct 1;23(19):5300-6. doi: 10.1016/j.bmcl.2013.07.071. , Epub 2013 Aug 9. PMID:23981898 doi:https://dx.doi.org/10.1016/j.bmcl.2013.07.071

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[2]

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@@ Line 1: / Line 1: @@
 ==Crystal Structure of Human Beta Secretase in Complex with Compound 11a==
 <StructureSection load='4lxa' size='340' side='right' caption='[[4lxa]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE, BACE1, 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=4lxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lxa RCSB], [http://www.ebi.ac.uk/pdbsum/4lxa 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=4lxa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lxa OCA], [http://pdbe.org/4lxa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lxa RCSB], [http://www.ebi.ac.uk/pdbsum/4lxa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lxa ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4lxa" style="background-color:#fffaf0;"></div>
 ==See Also==

4lxa: Difference between revisions

Revision as of 12:18, 5 August 2016

Crystal Structure of Human Beta Secretase in Complex with Compound 11a

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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