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| - | [[Image:2ewy.gif|left|200px]]<br /> | |
| - | <applet load="2ewy" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2ewy, resolution 3.10Å" /> | |
| - | '''Crystal structure of human BACE2 in complex with a hydroxyethylenamine transition-state inhibitor'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Crystal structure of human BACE2 in complex with a hydroxyethylenamine transition-state inhibitor== |
| - | BACE2 is a membrane-bound aspartic protease of the A1 family with a high, level of sequence homology to BACE1. While BACE1 is involved in the, generation of amyloid plaques in Alzheimer's disease by cleaving, Abeta-peptides from the amyloid precursor protein, the physiological, function of BACE2 is not well understood. BACE2 appears to be associated, with the early onset of dementia in patients with Down's syndrome, and it, has been shown to be highly expressed in breast cancers. Further, it may, participate in the function of normal and abnormal processes of human, muscle biology. Similar to other aspartic proteases, BACE2 is expressed as, an inactive zymogen requiring the cleavage of its pro-sequence during the, maturation process. We have produced mature BACE2 by expression of, pro-BACE2 in Escherichia coli as inclusion bodies, followed by refolding, and autocatalytic activation at pH 3.4. Using a C and N-terminally, truncated BACE2 variant, we were able to crystallize and determine the, crystal structure of mature BACE2 in complex with a hydroxyethylamine, transition-state mimetic inhibitor at 3.1 angstroms resolution. The, structure of BACE2 follows the general fold of A1 aspartic proteases., However, similar to BACE1, its C-terminal domain is significantly larger, than that of the other family members. Furthermore, the structure of BACE2, reveals differences in the S3, S2, S1' and S2' active site substrate, pockets as compared to BACE1, and allows, therefore, for a deeper, understanding of the structural features that may facilitate the design of, selective BACE1 or BACE2 inhibitors. | + | <StructureSection load='2ewy' size='340' side='right'caption='[[2ewy]], [[Resolution|resolution]] 3.10Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2ewy]] is a 4 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=2EWY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2EWY 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]] 3.1Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DBO:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHYLBENZYL)AMINO]PROPYL}DIBENZO[B,F]OXEPINE-10-CARBOXAMIDE'>DBO</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=2ewy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ewy OCA], [https://pdbe.org/2ewy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ewy RCSB], [https://www.ebi.ac.uk/pdbsum/2ewy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ewy ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/BACE2_HUMAN BACE2_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading 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. It has also been shown that it can cleave APP between residues 671 and 672.<ref>PMID:10591213</ref> <ref>PMID:11083922</ref> <ref>PMID:15857888</ref> <ref>PMID:11423558</ref> <ref>PMID:16816112</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ew/2ewy_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ewy ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | BACE2 is a membrane-bound aspartic protease of the A1 family with a high level of sequence homology to BACE1. While BACE1 is involved in the generation of amyloid plaques in Alzheimer's disease by cleaving Abeta-peptides from the amyloid precursor protein, the physiological function of BACE2 is not well understood. BACE2 appears to be associated with the early onset of dementia in patients with Down's syndrome, and it has been shown to be highly expressed in breast cancers. Further, it may participate in the function of normal and abnormal processes of human muscle biology. Similar to other aspartic proteases, BACE2 is expressed as an inactive zymogen requiring the cleavage of its pro-sequence during the maturation process. We have produced mature BACE2 by expression of pro-BACE2 in Escherichia coli as inclusion bodies, followed by refolding and autocatalytic activation at pH 3.4. Using a C and N-terminally truncated BACE2 variant, we were able to crystallize and determine the crystal structure of mature BACE2 in complex with a hydroxyethylamine transition-state mimetic inhibitor at 3.1 angstroms resolution. The structure of BACE2 follows the general fold of A1 aspartic proteases. However, similar to BACE1, its C-terminal domain is significantly larger than that of the other family members. Furthermore, the structure of BACE2 reveals differences in the S3, S2, S1' and S2' active site substrate pockets as compared to BACE1, and allows, therefore, for a deeper understanding of the structural features that may facilitate the design of selective BACE1 or BACE2 inhibitors. |
| | | | |
| - | ==About this Structure==
| + | Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor.,Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B J Mol Biol. 2006 Jan 13;355(2):249-61. Epub 2005 Nov 8. PMID:16305800<ref>PMID:16305800</ref> |
| - | 2EWY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with DBO as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Memapsin_1 Memapsin 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.45 3.4.23.45] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2EWY OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor., Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B, J Mol Biol. 2006 Jan 13;355(2):249-61. Epub 2005 Nov 8. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16305800 16305800]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 2ewy" style="background-color:#fffaf0;"></div> |
| - | [[Category: Memapsin 1]]
| + | |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Ostermann, N.]]
| + | |
| - | [[Category: DBO]]
| + | |
| - | [[Category: aspartic protease]]
| + | |
| - | [[Category: bace2]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:56:46 2007''
| + | ==See Also== |
| | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Ostermann N]] |
| Structural highlights
Function
BACE2_HUMAN Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves APP, between residues 690 and 691, leading 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. It has also been shown that it can cleave APP between residues 671 and 672.[1] [2] [3] [4] [5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACE2 is a membrane-bound aspartic protease of the A1 family with a high level of sequence homology to BACE1. While BACE1 is involved in the generation of amyloid plaques in Alzheimer's disease by cleaving Abeta-peptides from the amyloid precursor protein, the physiological function of BACE2 is not well understood. BACE2 appears to be associated with the early onset of dementia in patients with Down's syndrome, and it has been shown to be highly expressed in breast cancers. Further, it may participate in the function of normal and abnormal processes of human muscle biology. Similar to other aspartic proteases, BACE2 is expressed as an inactive zymogen requiring the cleavage of its pro-sequence during the maturation process. We have produced mature BACE2 by expression of pro-BACE2 in Escherichia coli as inclusion bodies, followed by refolding and autocatalytic activation at pH 3.4. Using a C and N-terminally truncated BACE2 variant, we were able to crystallize and determine the crystal structure of mature BACE2 in complex with a hydroxyethylamine transition-state mimetic inhibitor at 3.1 angstroms resolution. The structure of BACE2 follows the general fold of A1 aspartic proteases. However, similar to BACE1, its C-terminal domain is significantly larger than that of the other family members. Furthermore, the structure of BACE2 reveals differences in the S3, S2, S1' and S2' active site substrate pockets as compared to BACE1, and allows, therefore, for a deeper understanding of the structural features that may facilitate the design of selective BACE1 or BACE2 inhibitors.
Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor.,Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B J Mol Biol. 2006 Jan 13;355(2):249-61. Epub 2005 Nov 8. PMID:16305800[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999 Dec 2;402(6761):533-7. PMID:10591213 doi:10.1038/990107
- ↑ Hussain I, Powell DJ, Howlett DR, Chapman GA, Gilmour L, Murdock PR, Tew DG, Meek TD, Chapman C, Schneider K, Ratcliffe SJ, Tattersall D, Testa TT, Southan C, Ryan DM, Simmons DL, Walsh FS, Dingwall C, Christie G. ASP1 (BACE2) cleaves the amyloid precursor protein at the beta-secretase site. Mol Cell Neurosci. 2000 Nov;16(5):609-19. PMID:11083922 doi:10.1006/mcne.2000.0884
- ↑ Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W. Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. FASEB J. 2005 May;19(7):739-49. PMID:15857888 doi:10.1096/fj.04-3426com
- ↑ Yan R, Munzner JB, Shuck ME, Bienkowski MJ. BACE2 functions as an alternative alpha-secretase in cells. J Biol Chem. 2001 Sep 7;276(36):34019-27. Epub 2001 Jun 22. PMID:11423558 doi:10.1074/jbc.M105583200
- ↑ Sun X, He G, Song W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome. FASEB J. 2006 Jul;20(9):1369-76. PMID:16816112 doi:10.1096/fj.05-5632com
- ↑ Ostermann N, Eder J, Eidhoff U, Zink F, Hassiepen U, Worpenberg S, Maibaum J, Simic O, Hommel U, Gerhartz B. Crystal structure of human BACE2 in complex with a hydroxyethylamine transition-state inhibitor. J Mol Biol. 2006 Jan 13;355(2):249-61. Epub 2005 Nov 8. PMID:16305800 doi:10.1016/j.jmb.2005.10.027
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