5htz

From Proteopedia

(Difference between revisions)

Revision as of 08:32, 27 May 2020

BACE1 in complex with (S)-5-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-2,5-dimethyl-1,2,4-thiadiazinan-3-iminium 1,1-dioxide

Structural highlights

5htz is a 2 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:	5hu0, 5hu1
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

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Abeta levels in rats and nonhuman primates and CSF Abeta levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.,Scott JD, Li SW, Brunskill AP, Chen X, Cox K, Cumming JN, Forman M, Gilbert EJ, Hodgson RA, Hyde LA, Jiang Q, Iserloh U, Kazakevich I, Kuvelkar R, Mei H, Meredith J, Misiaszek J, Orth P, Rossiter LM, Slater M, Stone J, Strickland CO, Voigt JH, Wang G, Wang H, Wu Y, Greenlee WJ, Parker EM, Kennedy ME, Stamford AW J Med Chem. 2016 Dec 8;59(23):10435-10450. Epub 2016 Nov 18. PMID:27933948^[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
↑ Scott JD, Li SW, Brunskill AP, Chen X, Cox K, Cumming JN, Forman M, Gilbert EJ, Hodgson RA, Hyde LA, Jiang Q, Iserloh U, Kazakevich I, Kuvelkar R, Mei H, Meredith J, Misiaszek J, Orth P, Rossiter LM, Slater M, Stone J, Strickland CO, Voigt JH, Wang G, Wang H, Wu Y, Greenlee WJ, Parker EM, Kennedy ME, Stamford AW. Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease. J Med Chem. 2016 Dec 8;59(23):10435-10450. Epub 2016 Nov 18. PMID:27933948 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b00307

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/5htz"

@@ Line 1: / Line 1: @@
 ==BACE1 in complex with (S)-5-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-2,5-dimethyl-1,2,4-thiadiazinan-3-iminium 1,1-dioxide==
-<StructureSection load='5htz' size='340' side='right' caption='[[5htz]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='5htz' size='340' side='right'caption='[[5htz]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5htz]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HTZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HTZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5htz]] is a 2 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=5HTZ OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HTZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=66J:(3E,5S)-5-{3-CHLORO-5-[5-(PROP-1-YN-1-YL)PYRIDIN-3-YL]THIOPHEN-2-YL}-2,5-DIMETHYL-1,2,4-THIADIAZINAN-3-IMINE+1,1-DIOXIDE'>66J</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66J:(3E,5S)-5-{3-CHLORO-5-[5-(PROP-1-YN-1-YL)PYRIDIN-3-YL]THIOPHEN-2-YL}-2,5-DIMETHYL-1,2,4-THIADIAZINAN-3-IMINE+1,1-DIOXIDE'>66J</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5hu0|5hu0]], [[5hu1|5hu1]]</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=5htz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htz OCA], [http://pdbe.org/5htz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htz RCSB], [http://www.ebi.ac.uk/pdbsum/5htz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htz 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=5htz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5htz OCA], [http://pdbe.org/5htz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5htz RCSB], [http://www.ebi.ac.uk/pdbsum/5htz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5htz ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5htz" 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: Orth, P]]
-[[Category: Alzheimers']]
+[[Category: Alzheimerss']]
 [[Category: Aspartyl protease]]
 [[Category: Hydrolase]]
 [[Category: Hydrolase-hydrolase inhibitor complex]]

5htz

From Proteopedia

Revision as of 08:32, 27 May 2020

BACE1 in complex with (S)-5-(3-chloro-5-(5-(prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-2,5-dimethyl-1,2,4-thiadiazinan-3-iminium 1,1-dioxide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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