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4r92

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Revision as of 21:02, 5 August 2016

BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(isonicotinamido)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium

Structural highlights

4r92 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	4r8y, 4r91, 4r93, 4r95
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 synthesis of a series of iminoheterocycles and their structure-activity relationships (SAR) as inhibitors of the aspartyl protease BACE1 will be detailed. An effort to access the S3 subsite directly from the S1 subsite initially yielded compounds with sub-micromolar potency. A subset of compounds from this effort unexpectedly occupied a different binding site and displayed excellent BACE1 affinities. Select compounds from this subset acutely lowered Abeta40 levels upon subcutaneous and oral administration to rats.

Discovery of potent iminoheterocycle BACE1 inhibitors.,Caldwell JP, Mazzola RD, Durkin J, Chen J, Chen X, Favreau L, Kennedy M, Kuvelkar R, Lee J, McHugh N, McKittrick B, Orth P, Stamford A, Strickland C, Voigt J, Wang L, Zhang L, Zhang Q, Zhu Z Bioorg Med Chem Lett. 2014 Oct 23;24(23):5455-5459. doi:, 10.1016/j.bmcl.2014.10.006. PMID:25455483^[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
↑ Caldwell JP, Mazzola RD, Durkin J, Chen J, Chen X, Favreau L, Kennedy M, Kuvelkar R, Lee J, McHugh N, McKittrick B, Orth P, Stamford A, Strickland C, Voigt J, Wang L, Zhang L, Zhang Q, Zhu Z. Discovery of potent iminoheterocycle BACE1 inhibitors. Bioorg Med Chem Lett. 2014 Oct 23;24(23):5455-5459. doi:, 10.1016/j.bmcl.2014.10.006. PMID:25455483 doi:http://dx.doi.org/10.1016/j.bmcl.2014.10.006

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/4r92"

@@ Line 1: / Line 1: @@
 ==BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(isonicotinamido)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium==
 <StructureSection load='4r92' size='340' side='right' caption='[[4r92]], [[Resolution|resolution]] 1.71&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4r8y|4r8y]], [[4r91|4r91]], [[4r93|4r93]], [[4r95|4r95]]</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=4r92 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r92 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r92 RCSB], [http://www.ebi.ac.uk/pdbsum/4r92 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=4r92 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r92 OCA], [http://pdbe.org/4r92 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4r92 RCSB], [http://www.ebi.ac.uk/pdbsum/4r92 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4r92 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4r92" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta secretase|Beta secretase]]
 == References ==
 <references/>

4r92

From Proteopedia

Revision as of 21:02, 5 August 2016

BACE-1 in complex with (R)-4-(2-cyclohexylethyl)-4-(((1S,3R)-3-(isonicotinamido)cyclohexyl)methyl)-1-methyl-5-oxoimidazolidin-2-iminium

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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