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2wf4

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Revision as of 20:42, 9 February 2016

HUMAN BACE-1 IN COMPLEX WITH 6-ETHYL-1-METHYL-N-((1S)-2-OXO-1-(PHENYLMETHYL)-3-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PROPYL)-1,3,4,6-TETRAHYDRO(1,2)THIAZEPINO(5,4,3-CD)INDOLE-8-CARBOXAMIDE 2,2-DIOXIDE

Structural highlights

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

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 BACE-1 inhibitors proved unlikely to provide molecules that would lower amyloid in an animal model at low oral doses. This observation led us to the discovery of a second generation of inhibitors having nanomolar activity in a cell-based assay and with the potential for improved pharmacokinetic profiles. In this Letter, we describe our successful strategy for the optimization of oral bioavailability and also give insights into the design of compounds with the potential for improved brain penetration.

Second generation of BACE-1 inhibitors part 3: Towards non hydroxyethylamine transition state mimetics.,Charrier N, Clarke B, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, 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):3674-8. Epub 2009 Apr 5. PMID:19406640^[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, Cutler L, Demont E, Dingwall C, Dunsdon R, Hawkins J, Howes C, 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 3: Towards non hydroxyethylamine transition state mimetics. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3674-8. Epub 2009 Apr 5. PMID:19406640 doi:10.1016/j.bmcl.2009.03.149

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2wf4"

@@ Line 2: / Line 2: @@
 <StructureSection load='2wf4' size='340' side='right' caption='[[2wf4]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2wf4]] 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=2WF4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WF4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2wf4]] 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=2WF4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2WF4 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZY4:N-[(1S)-1-BENZYL-2,2-DIHYDROXY-3-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PROPYL]-6-ETHYL-1-METHYL-1,3,4,6-TETRAHYDRO[1,2]THIAZEPINO[5,4,3-CD]INDOLE-8-CARBOXAMIDE+2,2-DIOXIDE'>ZY4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1tqf|1tqf]], [[1xn3|1xn3]], [[1m4h|1m4h]], [[2vnm|2vnm]], [[2fdp|2fdp]], [[1xn2|1xn2]], [[2viy|2viy]], [[2va6|2va6]], [[2vie|2vie]], [[2vj6|2vj6]], [[2viz|2viz]], [[2b8l|2b8l]], [[1ym4|1ym4]], [[2va5|2va5]], [[1sgz|1sgz]], [[1ujk|1ujk]], [[2b8v|2b8v]], [[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]], [[2wf3|2wf3]], [[2wf1|2wf1]], [[2wf0|2wf0]], [[2wez|2wez]], [[2wf2|2wf2]]</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=2wf4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wf4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2wf4 RCSB], [http://www.ebi.ac.uk/pdbsum/2wf4 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=2wf4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2wf4 OCA], [http://pdbe.org/2wf4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2wf4 RCSB], [http://www.ebi.ac.uk/pdbsum/2wf4 PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 18: @@
     <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].
+</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=2wf4 ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 28: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2wf4" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 35: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Memapsin 2]]
 [[Category: Brien, A O]]

2wf4

From Proteopedia

Revision as of 20:42, 9 February 2016

HUMAN BACE-1 IN COMPLEX WITH 6-ETHYL-1-METHYL-N-((1S)-2-OXO-1-(PHENYLMETHYL)-3-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)PROPYL)-1,3,4,6-TETRAHYDRO(1,2)THIAZEPINO(5,4,3-CD)INDOLE-8-CARBOXAMIDE 2,2-DIOXIDE

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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