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5hdu

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BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium

Structural highlights

5hdu is a 2 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 1.58Å
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

We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2 pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Abeta40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Abeta in nonrodent preclinical species.

Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Abeta in Nonhuman Primates.,Mandal M, Wu Y, Misiaszek J, Li G, Buevich A, Caldwell JP, Liu X, Mazzola RD, Orth P, Strickland C, Voigt J, Wang H, Zhu Z, Chen X, Grzelak M, Hyde LA, Kuvelkar R, Leach PT, Terracina G, Zhang L, Zhang Q, Michener MS, Smith B, Cox K, Grotz D, Favreau L, Mitra K, Kazakevich I, McKittrick BA, Greenlee W, Kennedy ME, Parker EM, Cumming JN, Stamford AW J Med Chem. 2016 Apr 14;59(7):3231-48. doi: 10.1021/acs.jmedchem.5b01995. Epub, 2016 Mar 22. PMID:26937601^[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
↑ Mandal M, Wu Y, Misiaszek J, Li G, Buevich A, Caldwell JP, Liu X, Mazzola RD, Orth P, Strickland C, Voigt J, Wang H, Zhu Z, Chen X, Grzelak M, Hyde LA, Kuvelkar R, Leach PT, Terracina G, Zhang L, Zhang Q, Michener MS, Smith B, Cox K, Grotz D, Favreau L, Mitra K, Kazakevich I, McKittrick BA, Greenlee W, Kennedy ME, Parker EM, Cumming JN, Stamford AW. Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Abeta in Nonhuman Primates. J Med Chem. 2016 Apr 14;59(7):3231-48. doi: 10.1021/acs.jmedchem.5b01995. Epub, 2016 Mar 22. PMID:26937601 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b01995

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/5hdu"

Categories: Homo sapiens | Large Structures | Orth P

@@ Line 1: / Line 1: @@
 ==BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium==
-<StructureSection load='5hdu' size='340' side='right' caption='[[5hdu]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
+<StructureSection load='5hdu' size='340' side='right'caption='[[5hdu]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5hdu]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HDU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HDU FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5hdu]] is a 2 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=5HDU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HDU FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=60W:3-{5-[(2E,4AR,7AR)-6-(5-FLUORO-4-METHOXYPYRIMIDIN-2-YL)-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>60W</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 1.58&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5he5|5he5]], [[5he4|5he4]], [[5hdz|5hdz]], [[5hdx|5hdx]], [[5hdv|5hdv]], [[5he7|5he7]], [[5hd0|5hd0]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=60W:3-{5-[(2E,4AR,7AR)-6-(5-FLUORO-4-METHOXYPYRIMIDIN-2-YL)-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>60W</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5hdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hdu OCA], [https://pdbe.org/5hdu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hdu RCSB], [https://www.ebi.ac.uk/pdbsum/5hdu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hdu ProSAT]</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=5hdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hdu OCA], [http://pdbe.org/5hdu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hdu RCSB], [http://www.ebi.ac.uk/pdbsum/5hdu PDBsum]</span></td></tr>
 </table>
 == Function ==
-[[http://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 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 5hdu" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Memapsin 2]]
+[[Category: Homo sapiens]]
-[[Category: Orth, P]]
+[[Category: Large Structures]]
-[[Category: Alzheimers']]
+[[Category: Orth P]]
-[[Category: Aspartyl protease]]
-[[Category: Hydrolase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

5hdu

From Proteopedia

Current revision

BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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