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PDBsum entry 1lf3
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* Residue conservation analysis
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Enzyme class:
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E.C.3.4.23.39
- plasmepsin Ii.
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Reaction:
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Hydrolysis of the bonds linking certain hydrophobic residues in hemoglobin or globin. Also cleaves small molecules substrates such as Ala-Leu-Glu-Arg-Thr-Phe-|-Phe(NO(2))-Ser-Phe-Pro-Thr.
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DOI no:
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J Mol Biol
327:173-181
(2003)
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PubMed id:
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Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum.
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O.A.Asojo,
S.V.Gulnik,
E.Afonina,
B.Yu,
J.A.Ellman,
T.S.Haque,
A.M.Silva.
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ABSTRACT
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Malaria remains a human disease of global significance and a major cause of high
infant mortality in endemic nations. Parasites of the genus Plasmodium cause the
disease by degrading human hemoglobin as a source of amino acids for their
growth and maturation. Hemoglobin degradation is initiated by aspartic
proteases, termed plasmepsins, with a cleavage at the alpha-chain between
residues Phe33 and Leu34. Plasmepsin II is one of the four catalytically active
plasmepsins that has been identified in the food vacuole of Plasmodium
falciparum. Novel crystal structures of uncomplexed plasmepsin II as well as the
complex with a potent inhibitor have been refined with data extending to
resolution limits of 1.9A and 2.7A, and to R factors of 17% and 18%,
respectively. The inhibitor,
N-(3-[(2-benzo[1,3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl)-propionyl]-amino]-1-benzyl-2-(hydroxypropyl)-4-benzyloxy-3,5-dimethoxy-benzamide,
belongs to a family of potent non-peptidic inhibitors that have large P1'
groups. Such inhibitors could not be modeled into the binding cavity of the
structure of plasmepsin II in complex with pepstatin A. Our structures reveal
that the binding cavities of the new complex and uncomplexed plasmepsin II are
considerably more open than that of the pepstatin A complex, allowing for larger
heterocyclic groups in the P1', P2' and P2 positions. Both complexed and
uncomplexed plasmepsin II crystallized in space group P2, with one monomer in
the asymmetric unit. The structures show extensive interlocking of monomers
around the crystallographic axis of symmetry, with areas in excess of 2300A(2)
buried at the interface, and a loop of one monomer interacting with the binding
cavity of the 2-fold related monomer. Electron density for this loop is only
fully ordered in the complexed structure.
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Selected figure(s)
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Figure 1.
Figure 1. Ribbon diagram of the complex of plasmepsin II
with EH58 showing disulfide bridges, catalytic dyad, inhibitor,
flap, flexible loop and proline-rich loop in red, magenta,
white, blue, yellow and green, respectively.
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Figure 4.
Figure 4. Surface representations of a monomer of (a)
uncomplexed Plm II and Plm II in complex with (b) EH58 and (c)
pepstatin A, with the binding cavity of the complex with
pepstatin A revealing a much tighter embrace of the inhibitor.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2003,
327,
173-181)
copyright 2003.
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Figures were
selected
by the author.
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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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A.Mendoza,
S.Pérez-Silanes,
M.Quiliano,
A.Pabón,
S.Galiano,
G.González,
G.Garavito,
M.Zimic,
A.Vaisberg,
I.Aldana,
A.Monge,
and
E.Deharo
(2011).
Aryl piperazine and pyrrolidine as antimalarial agents. Synthesis and investigation of structure-activity relationships.
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Exp Parasitol,
128,
97.
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P.Bhaumik,
Y.Horimoto,
H.Xiao,
T.Miura,
K.Hidaka,
Y.Kiso,
A.Wlodawer,
R.Y.Yada,
and
A.Gustchina
(2011).
Crystal structures of the free and inhibited forms of plasmepsin I (PMI) from Plasmodium falciparum.
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J Struct Biol,
175,
73-84.
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PDB codes:
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P.A.Valiente,
A.Gil,
P.R.Batista,
E.R.Caffarena,
T.Pons,
and
P.G.Pascutti
(2010).
New parameterization approaches of the LIE method to improve free energy calculations of PlmII-Inhibitors complexes.
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J Comput Chem,
31,
2723-2734.
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T.Luksch,
A.Blum,
N.Klee,
W.E.Diederich,
C.A.Sotriffer,
and
G.Klebe
(2010).
Pyrrolidine derivatives as plasmepsin inhibitors: binding mode analysis assisted by molecular dynamics simulations of a highly flexible protein.
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ChemMedChem,
5,
443-454.
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A.H.Robbins,
B.M.Dunn,
M.Agbandje-McKenna,
and
R.McKenna
(2009).
Crystallographic evidence for noncoplanar catalytic aspartic acids in plasmepsin II resides in the Protein Data Bank.
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Acta Crystallogr D Biol Crystallogr,
65,
294-296.
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PDB code:
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D.L.Gardiner,
T.S.Skinner-Adams,
C.L.Brown,
K.T.Andrews,
C.M.Stack,
J.S.McCarthy,
J.P.Dalton,
and
K.R.Trenholme
(2009).
Plasmodium falciparum: new molecular targets with potential for antimalarial drug development.
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Expert Rev Anti Infect Ther,
7,
1087-1098.
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J.C.Kwan,
E.A.Eksioglu,
C.Liu,
V.J.Paul,
and
H.Luesch
(2009).
Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation.
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J Med Chem,
52,
5732-5747.
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N.Sturm,
E.Jortzik,
B.M.Mailu,
S.Koncarevic,
M.Deponte,
K.Forchhammer,
S.Rahlfs,
and
K.Becker
(2009).
Identification of proteins targeted by the thioredoxin superfamily in Plasmodium falciparum.
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PLoS Pathog,
5,
e1000383.
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P.Bhaumik,
H.Xiao,
C.L.Parr,
Y.Kiso,
A.Gustchina,
R.Y.Yada,
and
A.Wlodawer
(2009).
Crystal structures of the histo-aspartic protease (HAP) from Plasmodium falciparum.
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J Mol Biol,
388,
520-540.
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PDB codes:
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P.Liu,
M.R.Marzahn,
A.H.Robbins,
H.Gutiérrez-de-Terán,
D.Rodríguez,
S.H.McClung,
S.M.Stevens,
C.A.Yowell,
J.B.Dame,
R.McKenna,
and
B.M.Dunn
(2009).
Recombinant plasmepsin 1 from the human malaria parasite plasmodium falciparum: enzymatic characterization, active site inhibitor design, and structural analysis.
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Biochemistry,
48,
4086-4099.
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PDB code:
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R.Friedman,
and
A.Caflisch
(2009).
Discovery of plasmepsin inhibitors by fragment-based docking and consensus scoring.
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ChemMedChem,
4,
1317-1326.
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M.E.Popov,
M.A.Sten'gach,
and
N.S.Andreeva
(2008).
[Modeling of substrate and inhibitory complexes of histidine-aspartic protease]
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Bioorg Khim,
34,
422-429.
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M.Zürcher,
T.Gottschalk,
S.Meyer,
D.Bur,
and
F.Diederich
(2008).
Exploring the flap pocket of the antimalarial target plasmepsin II: the "55 % rule" applied to enzymes.
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ChemMedChem,
3,
237-240.
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P.A.Valiente,
P.R.Batista,
A.Pupo,
T.Pons,
A.Valencia,
and
P.G.Pascutti
(2008).
Predicting functional residues in Plasmodium falciparum plasmepsins by combining sequence and structural analysis with molecular dynamics simulations.
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Proteins,
73,
440-457.
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R.Friedman,
and
A.Caflisch
(2008).
Pepsinogen-like activation intermediate of plasmepsin II revealed by molecular dynamics analysis.
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Proteins,
73,
814-827.
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T.A.Binkowski,
and
A.Joachimiak
(2008).
Protein functional surfaces: global shape matching and local spatial alignments of ligand binding sites.
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BMC Struct Biol,
8,
45.
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T.Luksch,
N.S.Chan,
S.Brass,
C.A.Sotriffer,
G.Klebe,
and
W.E.Diederich
(2008).
Computer-aided design and synthesis of nonpeptidic plasmepsin II and IV inhibitors.
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ChemMedChem,
3,
1323-1336.
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R.E.Moose,
J.C.Clemente,
L.R.Jackson,
M.Ngo,
K.Wooten,
R.Chang,
A.Bennett,
S.Chakraborty,
C.A.Yowell,
J.B.Dame,
M.Agbandje-McKenna,
and
B.M.Dunn
(2007).
Analysis of binding interactions of pepsin inhibitor-3 to mammalian and malarial aspartic proteases.
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Biochemistry,
46,
14198-14205.
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C.Binkert,
M.Frigerio,
A.Jones,
S.Meyer,
C.Pesenti,
L.Prade,
F.Viani,
and
M.Zanda
(2006).
Replacement of isobutyl by trifluoromethyl in pepstatin A selectively affects inhibition of aspartic proteinases.
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Chembiochem,
7,
181-186.
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F.Hof,
A.Schütz,
C.Fäh,
S.Meyer,
D.Bur,
J.Liu,
D.E.Goldberg,
and
F.Diederich
(2006).
Starving the malaria parasite: inhibitors active against the aspartic proteases plasmepsins I, II, and IV.
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Angew Chem Int Ed Engl,
45,
2138-2141.
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J.C.Clemente,
L.Govindasamy,
A.Madabushi,
S.Z.Fisher,
R.E.Moose,
C.A.Yowell,
K.Hidaka,
T.Kimura,
Y.Hayashi,
Y.Kiso,
M.Agbandje-McKenna,
J.B.Dame,
B.M.Dunn,
and
R.McKenna
(2006).
Structure of the aspartic protease plasmepsin 4 from the malarial parasite Plasmodium malariae bound to an allophenylnorstatine-based inhibitor.
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Acta Crystallogr D Biol Crystallogr,
62,
246-252.
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PDB code:
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J.Liu,
E.S.Istvan,
and
D.E.Goldberg
(2006).
Hemoglobin-degrading plasmepsin II is active as a monomer.
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J Biol Chem,
281,
38682-38688.
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K.Ersmark,
B.Samuelsson,
and
A.Hallberg
(2006).
Plasmepsins as potential targets for new antimalarial therapy.
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Med Res Rev,
26,
626-666.
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K.T.Andrews,
D.P.Fairlie,
P.K.Madala,
J.Ray,
D.M.Wyatt,
P.M.Hilton,
L.A.Melville,
L.Beattie,
D.L.Gardiner,
R.C.Reid,
M.J.Stoermer,
T.Skinner-Adams,
C.Berry,
and
J.S.McCarthy
(2006).
Potencies of human immunodeficiency virus protease inhibitors in vitro against Plasmodium falciparum and in vivo against murine malaria.
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Antimicrob Agents Chemother,
50,
639-648.
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S.Weik,
T.Luksch,
A.Evers,
J.Böttcher,
C.A.Sotriffer,
A.Hasilik,
H.G.Löffler,
G.Klebe,
and
J.Rademann
(2006).
The potential of P1 site alterations in peptidomimetic protease inhibitors as suggested by virtual screening and explored by the use of C-C-coupling reagents.
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ChemMedChem,
1,
445-457.
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D.Muthas,
D.Nöteberg,
Y.A.Sabnis,
E.Hamelink,
L.Vrang,
B.Samuelsson,
A.Karlén,
and
A.Hallberg
(2005).
Synthesis, biological evaluation, and modeling studies of inhibitors aimed at the malarial proteases plasmepsins I and II.
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Bioorg Med Chem,
13,
5371-5390.
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E.S.Istvan,
and
D.E.Goldberg
(2005).
Distal substrate interactions enhance plasmepsin activity.
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J Biol Chem,
280,
6890-6896.
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L.Prade,
A.F.Jones,
C.Boss,
S.Richard-Bildstein,
S.Meyer,
C.Binkert,
and
D.Bur
(2005).
X-ray structure of plasmepsin II complexed with a potent achiral inhibitor.
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J Biol Chem,
280,
23837-23843.
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PDB code:
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M.M.Kesavulu,
A.S.Prakasha Gowda,
T.N.Ramya,
N.Surolia,
and
K.Suguna
(2005).
Plasmepsin inhibitors: design, synthesis, inhibitory studies and crystal structure analysis.
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J Pept Res,
66,
211-219.
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A.L.Omara-Opyene,
P.A.Moura,
C.R.Sulsona,
J.A.Bonilla,
C.A.Yowell,
H.Fujioka,
D.A.Fidock,
and
J.B.Dame
(2004).
Genetic disruption of the Plasmodium falciparum digestive vacuole plasmepsins demonstrates their functional redundancy.
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J Biol Chem,
279,
54088-54096.
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E.Alexov
(2004).
Calculating proton uptake/release and binding free energy taking into account ionization and conformation changes induced by protein-inhibitor association: application to plasmepsin, cathepsin D and endothiapepsin-pepstatin complexes.
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Proteins,
56,
572-584.
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N.Andreeva,
P.Bogdanovich,
I.Kashparov,
M.Popov,
and
M.Stengach
(2004).
Is histoaspartic protease a serine protease with a pepsin-like fold?
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Proteins,
55,
705-710.
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PDB code:
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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.
Where a reference describes a PDB structure, the PDB
codes are
shown on the right.
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Links
