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PDBsum entry 3k5c
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Hydrolase/hydrolase inhibitor
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PDB id
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3k5c
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Contents |
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* Residue conservation analysis
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Human bace-1 complex with nb-216
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Structure:
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Beta-secretase 1. Chain: a, b, c. Fragment: catalytic domain. Synonym: beta-site amyloid precursor protein cleaving enzyme 1, beta- site app cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, asp 2, asp2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bace, bace1, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 469008.
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Resolution:
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2.12Å
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R-factor:
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0.202
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R-free:
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0.220
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Authors:
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J.-M.Rondeau
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Key ref:
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A.Lerchner
et al.
(2010).
Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.
Bioorg Med Chem Lett,
20,
603-607.
PubMed id:
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Date:
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07-Oct-09
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Release date:
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02-Mar-10
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PROCHECK
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Headers
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References
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P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
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Seq:
Struc:
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501 a.a.
377 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Bioorg Med Chem Lett
20:603-607
(2010)
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PubMed id:
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Macrocyclic BACE-1 inhibitors acutely reduce Abeta in brain after po application.
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A.Lerchner,
R.Machauer,
C.Betschart,
S.Veenstra,
H.Rueeger,
C.McCarthy,
M.Tintelnot-Blomley,
A.L.Jaton,
S.Rabe,
S.Desrayaud,
A.Enz,
M.Staufenbiel,
P.Paganetti,
J.M.Rondeau,
U.Neumann.
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ABSTRACT
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A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency
on BACE-1 was rather high, the first set of compounds showed poor brain
permeation and high efflux in the MDRI-MDCK assay. The replacement of the
secondary benzylamino group with a phenylcyclopropylamino group maintained
potency on BACE-1, while P-glycoprotein-mediated efflux was significantly
reduced and brain permeation improved. Several compounds from this series
demonstrated acute reduction of Abeta in human APP-wildtype transgenic
(APP51/16) mice after oral administration.
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Links
