3u6a: Difference between revisions

Latest revision as of 10:31, 6 November 2024

Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors

Structural highlights

3u6a is a 3 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 2.199Å
Ligands:	18P, SO4
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

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.,Tresadern G, Delgado F, Delgado O, Gijsen H, Macdonald GJ, Moechars D, Rombouts F, Alexander R, Spurlino J, Van Gool M, Vega JA, Trabanco AA Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi:, 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20. PMID:22071305^[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
↑ Tresadern G, Delgado F, Delgado O, Gijsen H, Macdonald GJ, Moechars D, Rombouts F, Alexander R, Spurlino J, Van Gool M, Vega JA, Trabanco AA. Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors. Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi:, 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20. PMID:22071305 doi:10.1016/j.bmcl.2011.10.050

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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] Tresadern G, Delgado F, Delgado O, Gijsen H, Macdonald GJ, Moechars D, Rombouts F, Alexander R, Spurlino J, Van Gool M, Vega JA, Trabanco AA. Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors. Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi:, 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20. PMID:22071305 doi:10.1016/j.bmcl.2011.10.050

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='3u6a' size='340' side='right'caption='[[3u6a]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3u6a]] is a 3 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=3U6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U6A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3u6a]] is a 3 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=3U6A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3U6A FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=18P:N-{3-[(2R)-6-AMINO-2,4-DIMETHYL-3-OXO-2,3,4,5-TETRAHYDROPYRAZIN-2-YL]PHENYL}-5-CHLOROPYRIDINE-2-CARBOXAMIDE'>18P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.199&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=18P:N-{3-[(2R)-6-AMINO-2,4-DIMETHYL-3-OXO-2,3,4,5-TETRAHYDROPYRAZIN-2-YL]PHENYL}-5-CHLOROPYRIDINE-2-CARBOXAMIDE'>18P</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=3u6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3u6a OCA], [https://pdbe.org/3u6a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3u6a RCSB], [https://www.ebi.ac.uk/pdbsum/3u6a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3u6a 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>
+[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 ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Memapsin 2]]
+[[Category: Alexander RS]]
-[[Category: Alexander, R S]]
+[[Category: Spurlino JC]]
-[[Category: Spurlino, J C]]
-[[Category: Beta-site app cleaving enzyme 1]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

3u6a: Difference between revisions

Latest revision as of 10:31, 6 November 2024

Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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