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5enk

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Revision as of 07:06, 22 April 2020

Compound 18

Structural highlights

5enk is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5enm
Gene:	BACE1, BACE, 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

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Abeta reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Abeta Reduction in Rodents.,Wu YJ, Guernon J, Yang F, Snyder L, Shi J, Mcclure A, Rajamani R, Park H, Ng A, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA ACS Med Chem Lett. 2016 Jan 11;7(3):271-6. doi: 10.1021/acsmedchemlett.5b00432., eCollection 2016 Mar 10. PMID:26985314^[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
↑ Wu YJ, Guernon J, Yang F, Snyder L, Shi J, Mcclure A, Rajamani R, Park H, Ng A, Lewis H, Chang C, Camac D, Toyn JH, Ahlijanian MK, Albright CF, Macor JE, Thompson LA. Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Abeta Reduction in Rodents. ACS Med Chem Lett. 2016 Jan 11;7(3):271-6. doi: 10.1021/acsmedchemlett.5b00432., eCollection 2016 Mar 10. PMID:26985314 doi:http://dx.doi.org/10.1021/acsmedchemlett.5b00432

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/5enk"

@@ Line 1: / Line 1: @@
 ==Compound 18==
-<StructureSection load='5enk' size='340' side='right' caption='[[5enk]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
+<StructureSection load='5enk' size='340' side='right'caption='[[5enk]], [[Resolution|resolution]] 2.11&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5enk]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ENK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ENK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5enk]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ENK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5ENK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5QV:(4~{S},6~{S})-4-[2,4-BIS(FLUORANYL)-5-PYRIMIDIN-5-YL-PHENYL]-6-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-4-METHYL-5,6-DIHYDRO-1,3-THIAZIN-2-AMINE'>5QV</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5QV:(4~{S},6~{S})-4-[2,4-BIS(FLUORANYL)-5-PYRIMIDIN-5-YL-PHENYL]-6-(3,5-DIMETHYL-1,2-OXAZOL-4-YL)-4-METHYL-5,6-DIHYDRO-1,3-THIAZIN-2-AMINE'>5QV</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">[[5enm|5enm]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, 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=5enk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enk OCA], [http://pdbe.org/5enk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5enk RCSB], [http://www.ebi.ac.uk/pdbsum/5enk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5enk ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5enk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5enk OCA], [http://pdbe.org/5enk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5enk RCSB], [http://www.ebi.ac.uk/pdbsum/5enk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5enk ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5enk" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Memapsin 2]]
 [[Category: Lewis, H A]]
 [[Category: Bace]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]

5enk

From Proteopedia

Revision as of 07:06, 22 April 2020

Compound 18

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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