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[[Image:2vij.gif|left|200px]]


{{Structure
==Human BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(1,2,3,4- tetrahydro-1-naphthalenylamino)propyl)benzamide==
|PDB= 2vij |SIZE=350|CAPTION= <scene name='initialview01'>2vij</scene>, resolution 1.60&Aring;
<StructureSection load='2vij' size='340' side='right'caption='[[2vij]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
|SITE= <scene name='pdbsite=AC1:C44+Binding+Site+For+Chain+A'>AC1</scene> and <scene name='pdbsite=AC2:C44+Binding+Site+For+Chain+A'>AC2</scene>
== Structural highlights ==
|LIGAND= <scene name='pdbligand=C44:'>C44</scene>
<table><tr><td colspan='2'>[[2vij]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VIJ FirstGlance]. <br>
|ACTIVITY= [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]  
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C44:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(1S)-1,2,3,4-TETRAHYDRONAPHTHALEN-1-YLAMINO]PROPYL}-3-(1,1-DIOXIDO-1,2-THIAZINAN-2-YL)-5-(ETHYLAMINO)BENZAMIDE'>C44</scene></td></tr>
|GENE=  
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1m4h|1m4h]], [[1sgz|1sgz]], [[1w50|1w50]], [[1w51|1w51]], [[1xs7|1xs7]], [[1ym4|1ym4]], [[1fkn|1fkn]], [[1py1|1py1]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1ym2|1ym2]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]]</div></td></tr>
}}
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=2vij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vij OCA], [https://pdbe.org/2vij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vij RCSB], [https://www.ebi.ac.uk/pdbsum/2vij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vij ProSAT]</span></td></tr>
</table>
== Function ==
[[https://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</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/vi/2vij_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2vij ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.


'''HUMAN BACE-1 IN COMPLEX WITH 3-(1,1-DIOXIDOTETRAHYDRO-2H-1, 2-THIAZIN-2-YL)-5-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-1-(PHENYLMETHYL)-3-(1,2,3,4-TETRAHYDRO-1-NAPHTHALENYLAMINO) PROPYL)BENZAMIDE'''
BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells.,Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O'Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. Epub 2007 Dec 15. PMID:18171615<ref>PMID:18171615</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2vij" style="background-color:#fffaf0;"></div>


==Overview==
==See Also==
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.
*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 
== References ==
==About this Structure==
<references/>
2VIJ is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIJ OCA].
__TOC__
 
</StructureSection>
==Reference==
[[Category: Human]]
BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells., Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O'Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G, Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. Epub 2007 Dec 15. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18171615 18171615]
[[Category: Large Structures]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]
[[Category: Single protein]]
[[Category: Beswick, P]]
[[Category: Beswick, P.]]
[[Category: Brien, A O]]
[[Category: Brien, A O.]]
[[Category: Charrier, N]]
[[Category: Charrier, N.]]
[[Category: Clarke, B]]
[[Category: Clarke, B.]]
[[Category: Demont, E]]
[[Category: Demont, E.]]
[[Category: Dingwall, C]]
[[Category: Dingwall, C.]]
[[Category: Dunsdon, R]]
[[Category: Dunsdon, R.]]
[[Category: Faller, A]]
[[Category: Faller, A.]]
[[Category: Gleave, R]]
[[Category: Gleave, R.]]
[[Category: Hawkins, J]]
[[Category: Hawkins, J.]]
[[Category: Hussain, I]]
[[Category: Hussain, I.]]
[[Category: Johnson, C N]]
[[Category: Johnson, C.]]
[[Category: Macpherson, D]]
[[Category: Macpherson, D.]]
[[Category: Maile, G]]
[[Category: Maile, G.]]
[[Category: Matico, R]]
[[Category: Matico, R.]]
[[Category: Milner, P]]
[[Category: Milner, P.]]
[[Category: Mosley, J]]
[[Category: Mosley, J.]]
[[Category: Naylor, A]]
[[Category: Naylor, A.]]
[[Category: Redshaw, S]]
[[Category: Redshaw, S.]]
[[Category: Riddell, D]]
[[Category: Riddell, D.]]
[[Category: Rowland, P]]
[[Category: Rowland, P.]]
[[Category: Skidmore, J]]
[[Category: Skidmore, J.]]
[[Category: Smith, K J]]
[[Category: Smith, K.]]
[[Category: Soleil, V]]
[[Category: Soleil, V.]]
[[Category: Stanway, S]]
[[Category: Stanway, S.]]
[[Category: Stemp, G]]
[[Category: Stemp, G.]]
[[Category: Stuart, A]]
[[Category: Stuart, A.]]
[[Category: Sweitzer, S]]
[[Category: Sweitzer, S.]]
[[Category: Theobald, P]]
[[Category: Theobald, P.]]
[[Category: Vesey, D]]
[[Category: Vesey, D.]]
[[Category: Walter, D S]]
[[Category: Walter, D S.]]
[[Category: Ward, J]]
[[Category: Ward, J.]]
[[Category: Wayne, G]]
[[Category: Wayne, G.]]
[[Category: Alternative splicing]]
[[Category: C44]]
[[Category: Asp-2]]
[[Category: alternative splicing]]
[[Category: Aspartyl protease]]
[[Category: asp-2]]
[[Category: Bace-1]]
[[Category: aspartyl protease]]
[[Category: Beta-secretase]]
[[Category: bace-1]]
[[Category: Beta-site app cleaving enzyme]]
[[Category: beta-secretase]]
[[Category: Glycoprotein]]
[[Category: beta-site app cleaving enzyme]]
[[Category: Hydrolase]]
[[Category: glycoprotein]]
[[Category: Memapsin-2]]
[[Category: hydrolase]]
[[Category: Membrane]]
[[Category: memapsin-2]]
[[Category: Protease]]
[[Category: membrane]]
[[Category: Transmembrane]]
[[Category: protease]]
[[Category: Zymogen]]
[[Category: transmembrane]]
[[Category: zymogen]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:46:55 2008''

Latest revision as of 13:45, 7 July 2021

Human BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(1,2,3,4- tetrahydro-1-naphthalenylamino)propyl)benzamideHuman BACE-1 in complex with 3-(1,1-dioxidotetrahydro-2H-1,2-thiazin- 2-yl)-5-(ethylamino)-N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-3-(1,2,3,4- tetrahydro-1-naphthalenylamino)propyl)benzamide

Structural highlights

2vij 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:
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]

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

This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays.

BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells.,Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O'Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. Epub 2007 Dec 15. PMID:18171615[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ Beswick P, Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Faller A, Gleave R, Hawkins J, Hussain I, Johnson CN, MacPherson D, Maile G, Matico R, Milner P, Mosley J, Naylor A, O'Brien A, Redshaw S, Riddell D, Rowland P, Skidmore J, Soleil V, Smith KJ, Stanway S, Stemp G, Stuart A, Sweitzer S, Theobald P, Vesey D, Walter DS, Ward J, Wayne G. BACE-1 inhibitors part 3: identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1022-6. Epub 2007 Dec 15. PMID:18171615 doi:10.1016/j.bmcl.2007.12.020

2vij, resolution 1.60Å

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