2wf3: Difference between revisions

Revision as of 07:54, 12 December 2018

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

Structural highlights

2wf3 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:	GOL, ZY3
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, 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

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^[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
↑ 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

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] 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

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <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. 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>
+<table><tr><td colspan='2'>[[2wf3]] is a 1 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=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 id='ligand'><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></td></tr>
 <tr id='related'><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>
@@ Line 15: / Line 15: @@
 Check<jmol>
    <jmolCheckbox>
-     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/wf/2wf3_consurf.spt"</scriptWhenChecked>
+     <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>
@@ Line 37: / Line 37: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Memapsin 2]]
 [[Category: Brien, A O]]

2wf3: Difference between revisions

Revision as of 07:54, 12 December 2018

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

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

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