2wf3: Difference between revisions

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[[Image:2wf3.png|left|200px]]
==HUMAN BACE-1 IN COMPLEX WITH 6-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-3-(((3-(METHYLOXY)PHENYL)METHYL)AMINO)-1-(PHENYLMETHYL)PROPYL)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE 2,2-DIOXIDE==
<StructureSection load='2wf3' size='340' side='right' caption='[[2wf3]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2wf3]] is a 1 chain structure with 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=2WF3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WF3 FirstGlance]. <br>
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZY3:N-{(1S,2R)-1-BENZYL-2-HYDROXY-3-[(3-METHOXYBENZYL)AMINO]PROPYL}-6-(ETHYLAMINO)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE+2,2-DIOXIDE'>ZY3</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tqf|1tqf]], [[1xn3|1xn3]], [[2vnm|2vnm]], [[1m4h|1m4h]], [[2fdp|2fdp]], [[1xn2|1xn2]], [[2viy|2viy]], [[2va6|2va6]], [[2vie|2vie]], [[2vj6|2vj6]], [[2viz|2viz]], [[2b8l|2b8l]], [[1ym4|1ym4]], [[1sgz|1sgz]], [[2va5|2va5]], [[2b8v|2b8v]], [[1ujk|1ujk]], [[1fkn|1fkn]], [[1xs7|1xs7]], [[2vij|2vij]], [[2va7|2va7]], [[1ym2|1ym2]], [[2vkm|2vkm]], [[2vj9|2vj9]], [[2vnn|2vnn]], [[1py1|1py1]], [[1w50|1w50]], [[1ujj|1ujj]], [[2vj7|2vj7]], [[1w51|1w51]], [[2wf1|2wf1]], [[2wf4|2wf4]], [[2wf0|2wf0]], [[2wez|2wez]], [[2wf2|2wf2]]</td></tr>
<tr><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2wf3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wf3 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wf3 RCSB], [http://www.ebi.ac.uk/pdbsum/2wf3 PDBsum]</span></td></tr>
<table>
== 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/wf/2wf3_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/chain_selection.php?pdb_ID=2ata ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.


{{STRUCTURE_2wf3|  PDB=2wf3  |  SCENE=  }}
Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.,Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642<ref>PMID:19477642</ref>


===HUMAN BACE-1 IN COMPLEX WITH 6-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-3-(((3-(METHYLOXY)PHENYL)METHYL)AMINO)-1-(PHENYLMETHYL)PROPYL)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE 2,2-DIOXIDE===
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
{{ABSTRACT_PUBMED_19477642}}
 
==About this Structure==
[[2wf3]] is a 1 chain structure with 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=2WF3 OCA].


==See Also==
==See Also==
*[[Beta secretase|Beta secretase]]
*[[Beta secretase|Beta secretase]]
 
== References ==
==Reference==
<references/>
<ref group="xtra">PMID:019477642</ref><references group="xtra"/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]

Revision as of 09:38, 29 September 2014

HUMAN BACE-1 IN COMPLEX WITH 6-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-3-(((3-(METHYLOXY)PHENYL)METHYL)AMINO)-1-(PHENYLMETHYL)PROPYL)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE 2,2-DIOXIDEHUMAN BACE-1 IN COMPLEX WITH 6-(ETHYLAMINO)-N-((1S,2R)-2-HYDROXY-3-(((3-(METHYLOXY)PHENYL)METHYL)AMINO)-1-(PHENYLMETHYL)PROPYL)-1-METHYL-1,3,4,5-TETRAHYDRO-2,1-BENZOTHIAZEPINE-8-CARBOXAMIDE 2,2-DIOXIDE

Structural highlights

2wf3 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.
Ligands:,
Related:1tqf, 1xn3, 2vnm, 1m4h, 2fdp, 1xn2, 2viy, 2va6, 2vie, 2vj6, 2viz, 2b8l, 1ym4, 1sgz, 2va5, 2b8v, 1ujk, 1fkn, 1xs7, 2vij, 2va7, 1ym2, 2vkm, 2vj9, 2vnn, 1py1, 1w50, 1ujj, 2vj7, 1w51, 2wf1, 2wf4, 2wf0, 2wez, 2wf2
Activity:Memapsin 2, with EC number 3.4.23.46
Resources:FirstGlance, OCA, RCSB, PDBsum

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

Our first generation of hydroxyethylamine transition-state mimetic BACE-1 inhibitors allowed us to validate BACE-1 as a key target for Alzheimer's disease by demonstrating amyloid lowering in an animal model, albeit at rather high doses. Finding a molecule from this series which was active at lower oral doses proved elusive and demonstrated the need to find a novel series of inhibitors with improved pharmacokinetics. This Letter describes the discovery of such inhibitors.

Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent.,Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642[1]

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

See Also

References

  1. ↑ Charrier N, Clarke B, Demont E, Dingwall C, Dunsdon R, Hawkins J, Hubbard J, Hussain I, Maile G, Matico R, Mosley J, Naylor A, O'Brien A, Redshaw S, Rowland P, Soleil V, Smith KJ, Sweitzer S, Theobald P, Vesey D, Walter DS, Wayne G. Second generation of BACE-1 inhibitors part 2: Optimisation of the non-prime side substituent. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3669-73. Epub 2009 Apr 5. PMID:19477642 doi:10.1016/j.bmcl.2009.03.150

2wf3, resolution 2.08Å

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