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PDBsum entry 2vsq
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* Residue conservation analysis
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DOI no:
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Science
321:659-663
(2008)
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PubMed id:
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Crystal structure of the termination module of a nonribosomal peptide synthetase.
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A.Tanovic,
S.A.Samel,
L.O.Essen,
M.A.Marahiel.
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ABSTRACT
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Nonribosomal peptide synthetases (NRPSs) are modular multidomain enzymes that
act as an assembly line to catalyze the biosynthesis of complex natural
products. The crystal structure of the 144-kilodalton Bacillus subtilis
termination module SrfA-C was solved at 2.6 angstrom resolution. The adenylation
and condensation domains of SrfA-C associate closely to form a catalytic
platform, with their active sites on the same side of the platform. The peptidyl
carrier protein domain is flexibly tethered to this platform and thus can move
with its substrate-loaded 4'-phosphopantetheine arm between the active site of
the adenylation domain and the donor side of the condensation domain. The SrfA-C
crystal structure has implications for the rational redesign of NRPSs as a means
of producing novel bioactive peptides.
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Selected figure(s)
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Figure 1.
Fig. 1. Organization and overall structure of the synthetase
SrfA-C, the termination module of the surfactin biosynthesis
cluster from B. subtilis ATCC 21332. (A) The surfactin
biosynthetic operon [including srfA-A, 10,767 base pairs (bp);
srfA-B, 10,764 bp; srfA-C, 3825 bp] encoding the nonribosomal
peptide synthetases SrfA-A, B, and C and associated genes
(srfA-D and sfp). The chemical structure of the lipoheptapeptide
product surfactin is shown on the right. The yellow box
indicates the ring closure site between Leu^7 and the
β-hydroxyl group of the fatty acid catalyzed by SrfA-C. (B)
Schematic illustration of the terminal synthetase SrfA-C
comprising the condensation domain (C, gray), adenylation domain
(A, red and orange), peptidyl carrier protein domain (PCP,
green), and thioesterase domain (TE, brown). Linkers are blue;
the C-terminal tag helix is yellow. (C) Overall structure of
SrfA-C at 2.6 Å resolution. The C domain's catalytically
active residue His^147 and a leucine residue bound in the A
domain's active site are shown in space-filling representation.
Coloring of the domains is according to (B). See fig. S6 for
stereoviews of the total SrfA-C structure. All figures were made
with PYMOL 1.0 (20).
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Figure 5.
Fig. 5. Distances between the catalytic center of the PCP
domain at Ala^1003 and those of the C domain (His^147), the A
domain (Leu residue in the active site), and the TE domain
(Ser^1120), respectively. The dashed yellow circle has a radius
of 20 Å, corresponding to the distance that a
4'-phosphopantetheine cofactor can span. Because of perspective,
the interdomain distances appear shorter than they are.
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The above figures are
reprinted
by permission from the AAAs:
Science
(2008,
321,
659-663)
copyright 2008.
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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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T.Velkov,
J.Horne,
M.J.Scanlon,
B.Capuano,
E.Yuriev,
and
A.Lawen
(2011).
Characterization of the N-methyltransferase activities of the multifunctional polypeptide cyclosporin synthetase.
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Chem Biol,
18,
464-475.
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B.D.Ames,
and
C.T.Walsh
(2010).
Anthranilate-activating modules from fungal nonribosomal peptide assembly lines.
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Biochemistry,
49,
3351-3365.
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C.T.Walsh,
and
M.A.Fischbach
(2010).
Natural products version 2.0: connecting genes to molecules.
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J Am Chem Soc,
132,
2469-2493.
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I.Sainis,
D.Fokas,
K.Vareli,
A.G.Tzakos,
V.Kounnis,
and
E.Briasoulis
(2010).
Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs.
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Mar Drugs,
8,
629-657.
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L.Tran,
R.W.Broadhurst,
M.Tosin,
A.Cavalli,
and
K.J.Weissman
(2010).
Insights into protein-protein and enzyme-substrate interactions in modular polyketide synthases.
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Chem Biol,
17,
705-716.
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O.E.Zolova,
A.S.Mady,
and
S.Garneau-Tsodikova
(2010).
Recent developments in bisintercalator natural products.
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Biopolymers,
93,
777-790.
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S.Garneau-Tsodikova
(2010).
Special series: natural products at the core of drug discovery.
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Biopolymers,
93,
753-754.
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S.Kapur,
A.Y.Chen,
D.E.Cane,
and
C.Khosla
(2010).
Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase.
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Proc Natl Acad Sci U S A,
107,
22066-22071.
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T.V.Lee,
L.J.Johnson,
R.D.Johnson,
A.Koulman,
G.A.Lane,
J.S.Lott,
and
V.L.Arcus
(2010).
Structure of a eukaryotic nonribosomal peptide synthetase adenylation domain that activates a large hydroxamate amino acid in siderophore biosynthesis.
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J Biol Chem,
285,
2415-2427.
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PDB code:
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A.Koglin,
and
C.T.Walsh
(2009).
Structural insights into nonribosomal peptide enzymatic assembly lines.
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Nat Prod Rep,
26,
987.
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B.R.Villiers,
and
F.Hollfelder
(2009).
Mapping the limits of substrate specificity of the adenylation domain of TycA.
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Chembiochem,
10,
671-682.
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G.H.Hur,
J.L.Meier,
J.Baskin,
J.A.Codelli,
C.R.Bertozzi,
M.A.Marahiel,
and
M.D.Burkart
(2009).
Crosslinking studies of protein-protein interactions in nonribosomal peptide biosynthesis.
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Chem Biol,
16,
372-381.
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H.Jenke-Kodama,
and
E.Dittmann
(2009).
Bioinformatic perspectives on NRPS/PKS megasynthases: Advances and challenges.
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Nat Prod Rep,
26,
874-883.
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I.Ortel,
and
U.Keller
(2009).
Combinatorial assembly of simple and complex D-lysergic acid alkaloid peptide classes in the ergot fungus Claviceps purpurea.
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J Biol Chem,
284,
6650-6660.
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J.A.McIntosh,
M.S.Donia,
and
E.W.Schmidt
(2009).
Ribosomal peptide natural products: bridging the ribosomal and nonribosomal worlds.
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Nat Prod Rep,
26,
537-559.
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J.L.Meier,
and
M.D.Burkart
(2009).
The chemical biology of modular biosynthetic enzymes.
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Chem Soc Rev,
38,
2012-2045.
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M.Strieker,
and
M.A.Marahiel
(2009).
The structural diversity of acidic lipopeptide antibiotics.
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Chembiochem,
10,
607-616.
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P.Bernhardt,
and
S.E.O'Connor
(2009).
Opportunities for enzyme engineering in natural product biosynthesis.
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Curr Opin Chem Biol,
13,
35-42.
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S.Lin,
S.G.Van Lanen,
and
B.Shen
(2009).
A free-standing condensation enzyme catalyzing ester bond formation in C-1027 biosynthesis.
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Proc Natl Acad Sci U S A,
106,
4183-4188.
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S.M.Ma,
J.W.Li,
J.W.Choi,
H.Zhou,
K.K.Lee,
V.A.Moorthie,
X.Xie,
J.T.Kealey,
N.A.Da Silva,
J.C.Vederas,
and
Y.Tang
(2009).
Complete reconstitution of a highly reducing iterative polyketide synthase.
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Science,
326,
589-592.
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W.J.Ke,
B.Y.Chang,
T.P.Lin,
and
S.T.Liu
(2009).
Activation of the promoter of the fengycin synthetase operon by the UP element.
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J Bacteriol,
191,
4615-4623.
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J.L.Smith,
and
D.H.Sherman
(2008).
Biochemistry. An enzyme assembly line.
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Science,
321,
1304-1305.
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S.Kapur,
and
C.Khosla
(2008).
Biochemistry: Fit for an enzyme.
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Nature,
454,
832-833.
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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
code is
shown on the right.
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Links
