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5t1u

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Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

Structural highlights

5t1u 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 1.78Å
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 growing subset of beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.

Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.,Butler CR, Ogilvie K, Martinez-Alsina L, Barreiro G, Beck EM, Nolan CE, Atchison K, Benvenuti E, Buzon L, Doran S, Gonzales C, Helal CJ, Hou X, Hsu MH, Johnson EF, Lapham K, Lanyon L, Parris K, O'Neill BT, Riddell D, Robshaw A, Vajdos F, Brodney MA J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub, 2016 Dec 20. PMID:27997172^[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
↑ Butler CR, Ogilvie K, Martinez-Alsina L, Barreiro G, Beck EM, Nolan CE, Atchison K, Benvenuti E, Buzon L, Doran S, Gonzales C, Helal CJ, Hou X, Hsu MH, Johnson EF, Lapham K, Lanyon L, Parris K, O'Neill BT, Riddell D, Robshaw A, Vajdos F, Brodney MA. Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality. J Med Chem. 2017 Jan 12;60(1):386-402. doi: 10.1021/acs.jmedchem.6b01451. Epub, 2016 Dec 20. PMID:27997172 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01451

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/5t1u"

Categories: Homo sapiens | Large Structures | Parris KD | Vajdos F

@@ Line 1: / Line 1: @@
 ==Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality==
-<StructureSection load='5t1u' size='340' side='right' caption='[[5t1u]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
+<StructureSection load='5t1u' size='340' side='right'caption='[[5t1u]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5t1u]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T1U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T1U FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5t1u]] 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=5T1U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T1U FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=P6U:(4S)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4-METHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6U</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]] 1.78&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5t1w|5t1w]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene>, <scene name='pdbligand=P6U:(4S)-4-[2,4-DIFLUORO-5-({[1-(TRIFLUOROMETHYL)CYCLOPROPYL]AMINO}METHYL)PHENYL]-4-METHYL-5,6-DIHYDRO-4H-1,3-THIAZIN-2-AMINE'>P6U</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=5t1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1u OCA], [https://pdbe.org/5t1u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t1u RCSB], [https://www.ebi.ac.uk/pdbsum/5t1u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1u 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=5t1u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t1u OCA], [http://pdbe.org/5t1u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t1u RCSB], [http://www.ebi.ac.uk/pdbsum/5t1u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t1u ProSAT]</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 5t1u" 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: Parris, K D]]
+[[Category: Large Structures]]
-[[Category: Vajdos, F]]
+[[Category: Parris KD]]
-[[Category: Alzheimers']]
+[[Category: Vajdos F]]
-[[Category: Beta secretase]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Inhibitor]]

5t1u

From Proteopedia

Current revision

Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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