3tpj: Difference between revisions
New page: '''Unreleased structure''' The entry 3tpj is ON HOLD Authors: Xu,Y.C., Li,M.J., Greenblatt,H., Chen,T.T., Silman,I., Sussman,J.L. Description: APO STRUCTURE OF BACE1 |
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==APO structure of BACE1== | |||
<StructureSection load='3tpj' size='340' side='right'caption='[[3tpj]], [[Resolution|resolution]] 1.61Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[3tpj]] 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=3TPJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3TPJ 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]] 1.61Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=URE:UREA'>URE</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=3tpj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3tpj OCA], [https://pdbe.org/3tpj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3tpj RCSB], [https://www.ebi.ac.uk/pdbsum/3tpj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3tpj 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 == | |||
beta-Secretase (beta-site amyloid precursor protein-cleaving enzyme 1; BACE1) is a transmembrane aspartic protease that cleaves the beta-amyloid precursor protein en route to generation of the amyloid beta-peptide (Abeta) that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus a prime target for the development of inhibitors which may serve as drugs in the treatment and/or prevention of Alzheimer's disease. In the following determination of the crystal structures of both apo and complexed BACE1, structural analysis of all crystal structures of BACE1 deposited in the PDB and molecular dynamics (MD) simulations of monomeric and `dimeric' BACE1 were used to study conformational changes in the active-site region of the enzyme. It was observed that a flap able to cover the active site is the most flexible region, adopting multiple conformational states in the various crystal structures. Both the presence or absence of an inhibitor within the active site and the crystal packing are shown to influence the flap's conformation. An open conformation of the flap is mostly observed in the apo structures, while direct hydrogen-bonding interaction between main-chain atoms of the flap and the inhibitor is a prerequisite for the flap to adopt a closed conformation in the crystal structures of complexes. Thus, a systematic study of the conformational flexibility of the enzyme may not only contribute to structure-based drug design of BACE1 inhibitors and of other targets with flexible conformations, but may also help to better understand the mechanistic events associated with the binding of substrates and inhibitors to the enzyme. | |||
Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations.,Xu Y, Li MJ, Greenblatt H, Chen W, Paz A, Dym O, Peleg Y, Chen T, Shen X, He J, Jiang H, Silman I, Sussman JL Acta Crystallogr D Biol Crystallogr. 2012 Jan;68(Pt 1):13-25. Epub 2011 Dec 9. PMID:22194329<ref>PMID:22194329</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3tpj" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta secretase|Beta secretase]] | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Chen TT]] | |||
[[Category: Greenblatt H]] | |||
[[Category: Li MJ]] | |||
[[Category: Silman I]] | |||
[[Category: Sussman JL]] | |||
[[Category: Xu YC]] | |||
Latest revision as of 20:33, 1 November 2023
APO structure of BACE1APO structure of BACE1
Structural highlights
FunctionBACE1_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 PubMedbeta-Secretase (beta-site amyloid precursor protein-cleaving enzyme 1; BACE1) is a transmembrane aspartic protease that cleaves the beta-amyloid precursor protein en route to generation of the amyloid beta-peptide (Abeta) that is believed to be responsible for the Alzheimer's disease amyloid cascade. It is thus a prime target for the development of inhibitors which may serve as drugs in the treatment and/or prevention of Alzheimer's disease. In the following determination of the crystal structures of both apo and complexed BACE1, structural analysis of all crystal structures of BACE1 deposited in the PDB and molecular dynamics (MD) simulations of monomeric and `dimeric' BACE1 were used to study conformational changes in the active-site region of the enzyme. It was observed that a flap able to cover the active site is the most flexible region, adopting multiple conformational states in the various crystal structures. Both the presence or absence of an inhibitor within the active site and the crystal packing are shown to influence the flap's conformation. An open conformation of the flap is mostly observed in the apo structures, while direct hydrogen-bonding interaction between main-chain atoms of the flap and the inhibitor is a prerequisite for the flap to adopt a closed conformation in the crystal structures of complexes. Thus, a systematic study of the conformational flexibility of the enzyme may not only contribute to structure-based drug design of BACE1 inhibitors and of other targets with flexible conformations, but may also help to better understand the mechanistic events associated with the binding of substrates and inhibitors to the enzyme. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynamics simulations.,Xu Y, Li MJ, Greenblatt H, Chen W, Paz A, Dym O, Peleg Y, Chen T, Shen X, He J, Jiang H, Silman I, Sussman JL Acta Crystallogr D Biol Crystallogr. 2012 Jan;68(Pt 1):13-25. Epub 2011 Dec 9. PMID:22194329[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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