4x2l

From Proteopedia

(Difference between revisions)

Revision as of 00:08, 26 January 2017

Crystal structure of human BACE-1 bound to Compound 6

Structural highlights

4x2l is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
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 identification of centrally efficacious beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired ADME properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related Cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Oral administration of these inhibitors exhibit robust brain availability and are efficacious in lowering central Abeta levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Abeta-derived plaques. Most importantly, evaluation of 36 in a two-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors.

Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design.,Butler CR, Brodney MA, Beck EM, Barreiro G, Nolan CE, Pan F, Vajdos FF, Parris K, Varghese AH, Helal CJ, Lira R, Doran SD, Riddell D, Buzon LM, Dutra JK, Martinez-Alsina LA, Ogilvie K, Murray JC, Young JM, Atchison K, Robshaw A, Gonzales C, Wang J, Zhang Y, O'Neill BT J Med Chem. 2015 Feb 19. PMID:25695670^[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
↑ Butler CR, Brodney MA, Beck EM, Barreiro G, Nolan CE, Pan F, Vajdos FF, Parris K, Varghese AH, Helal CJ, Lira R, Doran SD, Riddell D, Buzon LM, Dutra JK, Martinez-Alsina LA, Ogilvie K, Murray JC, Young JM, Atchison K, Robshaw A, Gonzales C, Wang J, Zhang Y, O'Neill BT. Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design. J Med Chem. 2015 Feb 19. PMID:25695670 doi:http://dx.doi.org/10.1021/jm501833t

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/4x2l"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human BACE-1 bound to Compound 6==
 <StructureSection load='4x2l' size='340' side='right' caption='[[4x2l]], [[Resolution|resolution]] 2.55&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3WP:(4S)-4-(2,4-DIFLUOROPHENYL)-4-METHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>3WP</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></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=4x2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x2l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x2l RCSB], [http://www.ebi.ac.uk/pdbsum/4x2l 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=4x2l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x2l OCA], [http://pdbe.org/4x2l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4x2l RCSB], [http://www.ebi.ac.uk/pdbsum/4x2l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4x2l ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4x2l" style="background-color:#fffaf0;"></div>
 ==See Also==

4x2l

From Proteopedia

Revision as of 00:08, 26 January 2017

Crystal structure of human BACE-1 bound to Compound 6

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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