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7d2v

From Proteopedia

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Crystal Structure of BACE1 in complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-5,6-dihydro-2H-1lambda6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide

Structural highlights

7d2v 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 2.1Å
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

BACE1 is an attractive target for disease-modifying treatment of Alzheimer's disease. BACE2, having high homology around the catalytic site, poses a critical challenge to identifying selective BACE1 inhibitors. Recent evidence indicated that BACE2 has various roles in peripheral tissues and the brain, and therefore, the chronic use of nonselective inhibitors may cause side effects derived from BACE2 inhibition. Crystallographic analysis of the nonselective inhibitor verubecestat identified explicit water molecules with different levels of free energy in the S2' pocket. Structure-based design targeting them enabled the identification of propynyl oxazine 3 with improved selectivity. Further optimization efforts led to the discovery of compound 6 with high selectivity. The cocrystal structures of 7, a close analogue of 6, bound to BACE1 and BACE2 confirmed that one of the explicit water molecules is displaced by the propynyl group, suggesting that the difference in the relative water displacement cost may contribute to the improved selectivity.

Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2.,Fujimoto K, Yoshida S, Tadano G, Asada N, Fuchino K, Suzuki S, Matsuoka E, Yamamoto T, Yamamoto S, Ando S, Kanegawa N, Tonomura Y, Ito H, Moechars D, Rombouts FJR, Gijsen HJM, Kusakabe KI J Med Chem. 2021 Mar 25;64(6):3075-3085. doi: 10.1021/acs.jmedchem.0c01858. Epub , 2021 Mar 15. PMID:33719429^[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
↑ Fujimoto K, Yoshida S, Tadano G, Asada N, Fuchino K, Suzuki S, Matsuoka E, Yamamoto T, Yamamoto S, Ando S, Kanegawa N, Tonomura Y, Ito H, Moechars D, Rombouts FJR, Gijsen HJM, Kusakabe KI. Structure-Based Approaches to Improving Selectivity through Utilizing Explicit Water Molecules: Discovery of Selective beta-Secretase (BACE1) Inhibitors over BACE2. J Med Chem. 2021 Mar 25;64(6):3075-3085. doi: 10.1021/acs.jmedchem.0c01858. Epub , 2021 Mar 15. PMID:33719429 doi:http://dx.doi.org/10.1021/acs.jmedchem.0c01858

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/7d2v"

@@ Line 3: / Line 3: @@
 <StructureSection load='7d2v' size='340' side='right'caption='[[7d2v]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7d2v]] is a 1 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=7D2V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D2V FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7d2v]] 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=7D2V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D2V FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66F:N-{3-[(5R)-3-AMINO-2,5-DIMETHYL-1,1-DIOXIDO-5,6-DIHYDRO-2H-1,2,4-THIADIAZIN-5-YL]-4-FLUOROPHENYL}-5-FLUOROPYRIDINE-2-CARBOXAMIDE'>66F</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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]] 2.1&#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=66F:N-{3-[(5R)-3-AMINO-2,5-DIMETHYL-1,1-DIOXIDO-5,6-DIHYDRO-2H-1,2,4-THIADIAZIN-5-YL]-4-FLUOROPHENYL}-5-FLUOROPYRIDINE-2-CARBOXAMIDE'>66F</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=7d2v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d2v OCA], [https://pdbe.org/7d2v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d2v RCSB], [https://www.ebi.ac.uk/pdbsum/7d2v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d2v 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 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 7d2v" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Memapsin 2]]
+[[Category: Ando S]]
-[[Category: Ando, S]]
+[[Category: Asada N]]
-[[Category: Asada, N]]
+[[Category: Fuchino K]]
-[[Category: Fuchino, K]]
+[[Category: Fujimoto K]]
-[[Category: Fujimoto, K]]
+[[Category: Gijsen HJM]]
-[[Category: Gijsen, H J.M]]
+[[Category: Ito H]]
-[[Category: Ito, H]]
+[[Category: Kanegawa N]]
-[[Category: Kanegawa, N]]
+[[Category: Kusakabe KI]]
-[[Category: Kusakabe, K I]]
+[[Category: Matsuoka E]]
-[[Category: Matsuoka, E]]
+[[Category: Moechars D]]
-[[Category: Moechars, D]]
+[[Category: Rombouts FJR]]
-[[Category: Rombouts, F J.R]]
+[[Category: Suzuki S]]
-[[Category: Suzuki, S]]
+[[Category: Tadano G]]
-[[Category: Tadano, G]]
+[[Category: Tonomura Y]]
-[[Category: Tonomura, Y]]
+[[Category: Yamamoto S]]
-[[Category: Yamamoto, S]]
+[[Category: Yamamoto T]]
-[[Category: Yamamoto, T]]
+[[Category: Yoshida S]]
-[[Category: Yoshida, S]]
-[[Category: Bace1]]
-[[Category: Hydrolase]]

7d2v

From Proteopedia

Current revision

Crystal Structure of BACE1 in complex with N-{3-[(5R)-3-amino-2,5-dimethyl-1,1-dioxo-5,6-dihydro-2H-1lambda6,2,4-thiadiazin-5-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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