4dpf

From Proteopedia

(Difference between revisions)

Current revision

BACE-1 in complex with a HEA-macrocyclic type inhibitor

Structural highlights

4dpf 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.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:
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]

Publication Abstract from PubMed

A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.

Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.,Sandgren V, Agback T, Johansson PO, Lindberg J, Kvarnstrom I, Samuelsson B, Belda O, Dahlgren A Bioorg Med Chem. 2012 Jul 15;20(14):4377-89. Epub 2012 May 24. PMID:22698785^[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
↑ Sandgren V, Agback T, Johansson PO, Lindberg J, Kvarnstrom I, Samuelsson B, Belda O, Dahlgren A. Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes. Bioorg Med Chem. 2012 Jul 15;20(14):4377-89. Epub 2012 May 24. PMID:22698785 doi:10.1016/j.bmc.2012.05.039

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4dpf"

Categories: Homo sapiens | Large Structures | Borkakoti N | Derbyshire D | Lindberg J

@@ Line 1: / Line 1: @@
-[[Image:4dpf.png|left|200px]]
-{{STRUCTURE_4dpf|  PDB=4dpf  |  SCENE=  }}
+==BACE-1 in complex with a HEA-macrocyclic type inhibitor==
+<StructureSection load='4dpf' size='340' side='right'caption='[[4dpf]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4dpf]] is a 1 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=4DPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DPF 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]] 1.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0LG:N-[(4S,8E,11S)-4-[(1R)-1-HYDROXY-2-{[3-(PROPAN-2-YL)BENZYL]AMINO}ETHYL]-2,13-DIOXO-11-PHENYL-6-OXA-3,12-DIAZABICYCLO[12.3.1]OCTADECA-1(18),8,14,16-TETRAEN-16-YL]-N-METHYLMETHANESULFONAMIDE'>0LG</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=4dpf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4dpf OCA], [https://pdbe.org/4dpf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4dpf RCSB], [https://www.ebi.ac.uk/pdbsum/4dpf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4dpf 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>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+A series of P1-P3 linked macrocyclic BACE-1 inhibitors containing a hydroxyethylamine (HEA) isostere scaffold has been synthesized. All inhibitors comprise a toluene or N-phenylmethanesulfonamide P2 moiety. Excellent BACE-1 potencies, both in enzymatic and cell-based assays, were observed in this series of target compounds, with the best candidates displaying cell-based IC(50) values in the low nanomolar range. As an attempt to improve potency, a phenyl substituent aiming at the S3 subpocket was introduced in the macrocyclic ring. X-ray analyzes were performed on selected compounds, and enzyme-inhibitor interactions are discussed.
-===BACE-1 in complex with a HEA-macrocyclic type inhibitor===
+Highly potent macrocyclic BACE-1 inhibitors incorporating a hydroxyethylamine core: Design, synthesis and X-ray crystal structures of enzyme inhibitor complexes.,Sandgren V, Agback T, Johansson PO, Lindberg J, Kvarnstrom I, Samuelsson B, Belda O, Dahlgren A Bioorg Med Chem. 2012 Jul 15;20(14):4377-89. Epub 2012 May 24. PMID:22698785<ref>PMID:22698785</ref>
-{{ABSTRACT_PUBMED_22698785}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4dpf" style="background-color:#fffaf0;"></div>
-==About this Structure==
+==See Also==
-[[4dpf]] 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=4DPF OCA].
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:022698785</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Homo sapiens]]
-[[Category: Memapsin 2]]
+[[Category: Large Structures]]
-[[Category: Borkakoti, N.]]
+[[Category: Borkakoti N]]
-[[Category: Derbyshire, D.]]
+[[Category: Derbyshire D]]
-[[Category: Lindberg, J.]]
+[[Category: Lindberg J]]
-[[Category: Asp2]]
-[[Category: Bace]]
-[[Category: Bace1]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Macrocycle]]

4dpf

From Proteopedia

Current revision

BACE-1 in complex with a HEA-macrocyclic type inhibitor

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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