6jt3

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide

Structural highlights

6jt3 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 2.4Å
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

Genetic evidence points to deposition of amyloid-beta (Abeta) as a causal factor for Alzheimer's disease. Abeta generation is initiated when beta-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Abeta reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Abeta reduction of 80% at trough level.

Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose.,Tadano G, Komano K, Yoshida S, Suzuki S, Nakahara K, Fuchino K, Fujimoto K, Matsuoka E, Yamamoto T, Asada N, Ito H, Sakaguchi G, Kanegawa N, Kido Y, Ando S, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Van Den Bergh A, Austin N, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140. Epub, 2019 Oct 8. PMID:31549838^[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
↑ Tadano G, Komano K, Yoshida S, Suzuki S, Nakahara K, Fuchino K, Fujimoto K, Matsuoka E, Yamamoto T, Asada N, Ito H, Sakaguchi G, Kanegawa N, Kido Y, Ando S, Fukushima T, Teisman A, Urmaliya V, Dhuyvetter D, Borghys H, Van Den Bergh A, Austin N, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI. Discovery of an Extremely Potent Thiazine-Based beta-Secretase Inhibitor with Reduced Cardiovascular and Liver Toxicity at a Low Projected Human Dose. J Med Chem. 2019 Oct 24;62(20):9331-9337. doi: 10.1021/acs.jmedchem.9b01140. Epub, 2019 Oct 8. PMID:31549838 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01140

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/6jt3"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[6jt3]] 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=6JT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6JT3 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]] 2.4&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C83:N-[3-[(4R,5R,6R)-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide'>C83</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C83:~{N}-[3-[(4~{R},5~{R},6~{R})-2-azanyl-5-fluoranyl-4,6-dimethyl-5,6-dihydro-1,3-thiazin-4-yl]-4-fluoranyl-phenyl]-5-(fluoranylmethoxy)pyrazine-2-carboxamide'>C83</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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=6jt3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6jt3 OCA], [https://pdbe.org/6jt3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6jt3 RCSB], [https://www.ebi.ac.uk/pdbsum/6jt3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6jt3 ProSAT]</span></td></tr>
 </table>

6jt3

From Proteopedia

Current revision

Crystal Structure of BACE1 in complex with N-{3-[(4R,5R,6R)-2-amino-5-fluoro-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-4-yl]-4-fluorophenyl}-5-(fluoromethoxy)pyrazine-2-carboxamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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