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PDBsum entry 1ym2
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Hydrolase/hydrolase inhibitor
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PDB id
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1ym2
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of human beta secretase complexed with nvp-aur200
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Structure:
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Beta-secretase 1. Chain: a, b, c. Fragment: unp residues 48-447. Synonym: beta-site app cleaving enzyme 1, beta-site amyloid precursor protein cleaving enzyme 1, aspartyl protease 2, asp 2, asp2, membrane-associated aspartic protease 2, memapsin-2. Engineered: yes. Nvp-aur200 inhibitor. Chain: x, y, z.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes
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Resolution:
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2.05Å
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R-factor:
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0.215
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R-free:
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0.237
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Authors:
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S.Hanessian,H.Yun,Y.Hou,G.Yang,M.Bayrakdarian,E.Therrien, N.Moitessier,S.Roggo,S.Veenstra
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Key ref:
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S.Hanessian
et al.
(2005).
Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics.
J Med Chem,
48,
5175-5190.
PubMed id:
DOI:
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Date:
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20-Jan-05
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Release date:
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17-Jan-06
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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.
376 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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DOI no:
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J Med Chem
48:5175-5190
(2005)
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PubMed id:
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Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics.
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S.Hanessian,
H.Yun,
Y.Hou,
G.Yang,
M.Bayrakdarian,
E.Therrien,
N.Moitessier,
S.Roggo,
S.Veenstra,
M.Tintelnot-Blomley,
J.M.Rondeau,
C.Ostermeier,
A.Strauss,
P.Ramage,
P.Paganetti,
U.Neumann,
C.Betschart.
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ABSTRACT
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Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh
heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a
series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1
spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of
the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent
truncated analogue 5 with good selectivity over Cathepsin D. Using the same
backbone replacement concept, a series of cyclopentane, cyclopentanone,
tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with
considerable variation at the P and P' sites. The cyclopentanone and
2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray
cocrystal structures of two analogues 5 and 45 revealed excellent convergence
with the original inhibitor 1 structure while providing new insights into other
interactions which could be exploited for future modifications.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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S.John,
S.Thangapandian,
S.Sakkiah,
and
K.W.Lee
(2011).
Potent BACE-1 inhibitor design using pharmacophore modeling, in silico screening and molecular docking studies.
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BMC Bioinformatics,
12,
S28.
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E.Viayna,
T.Gómez,
C.Galdeano,
L.Ramírez,
M.Ratia,
A.Badia,
M.V.Clos,
E.Verdaguer,
F.Junyent,
A.Camins,
M.Pallàs,
M.Bartolini,
F.Mancini,
V.Andrisano,
M.P.Arce,
M.I.Rodríguez-Franco,
A.Bidon-Chanal,
F.J.Luque,
P.Camps,
and
D.Muñoz-Torrero
(2010).
Novel huprine derivatives with inhibitory activity toward β-amyloid aggregation and formation as disease-modifying anti-alzheimer drug candidates.
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ChemMedChem,
5,
1855-1870.
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K.B.Kegel,
E.Sapp,
J.Alexander,
P.Reeves,
D.Bleckmann,
L.Sobin,
N.Masso,
A.Valencia,
H.Jeong,
D.Krainc,
J.Palacino,
D.Curtis,
R.Kuhn,
C.Betschart,
M.Sena-Esteves,
N.Aronin,
P.Paganetti,
and
M.Difiglia
(2010).
Huntingtin cleavage product A forms in neurons and is reduced by gamma-secretase inhibitors.
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Mol Neurodegener,
5,
58.
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C.E.Hunt,
and
A.J.Turner
(2009).
Cell biology, regulation and inhibition of beta-secretase (BACE-1).
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FEBS J,
276,
1845-1859.
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C.Mulakala,
and
Y.N.Kaznessis
(2009).
Path-integral method for predicting relative binding affinities of protein-ligand complexes.
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J Am Chem Soc,
131,
4521-4528.
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Y.P.Zhu,
K.Xiao,
H.P.Yu,
L.P.Ma,
B.Xiong,
H.Y.Zhang,
X.Wang,
J.Y.Li,
J.Li,
and
J.K.Shen
(2009).
Discovery of potent beta-secretase (bace-1) inhibitors by the synthesis of isophthalamide-containing hybrids.
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Acta Pharmacol Sin,
30,
259-269.
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Y.Shimmyo,
T.Kihara,
A.Akaike,
T.Niidome,
and
H.Sugimoto
(2008).
Multifunction of myricetin on Abeta: Neuroprotection via a conformational change of Abeta and reduction of Abeta via the interference of secretases.
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J Neurosci Res,
86,
368-377.
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I.Hussain,
J.Hawkins,
D.Harrison,
C.Hille,
G.Wayne,
L.Cutler,
T.Buck,
D.Walter,
E.Demont,
C.Howes,
A.Naylor,
P.Jeffrey,
M.I.Gonzalez,
C.Dingwall,
A.Michel,
S.Redshaw,
and
J.B.Davis
(2007).
Oral administration of a potent and selective non-peptidic BACE-1 inhibitor decreases beta-cleavage of amyloid precursor protein and amyloid-beta production in vivo.
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J Neurochem,
100,
802-809.
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C.L.Masters,
R.Cappai,
K.J.Barnham,
and
V.L.Villemagne
(2006).
Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics.
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J Neurochem,
97,
1700-1725.
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P.R.Mittl,
and
M.G.Grütter
(2006).
Opportunities for structure-based design of protease-directed drugs.
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Curr Opin Struct Biol,
16,
769-775.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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