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PDBsum entry 1xr1
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* Residue conservation analysis
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PDB id:
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Transferase
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Title:
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Crystal structure of hpim-1 kinase in complex with amp-pnp at 2.1 a resolution
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Structure:
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Proto-oncogene serine/threonine-protein kinase pim-1. Chain: a. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: pim1. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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2.10Å
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R-factor:
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0.267
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R-free:
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0.301
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Authors:
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K.C.Qian,L.Wang,E.R.Hickey,J.Studts,K.Barringer,C.Peng,A.Kronkaitis, J.Li,A.White,S.Mische,B.Farmer
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Key ref:
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K.C.Qian
et al.
(2005).
Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase.
J Biol Chem,
280,
6130-6137.
PubMed id:
DOI:
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Date:
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13-Oct-04
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Release date:
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09-Nov-04
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PROCHECK
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Headers
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References
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P11309
(PIM1_HUMAN) -
Serine/threonine-protein kinase pim-1 from Homo sapiens
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Seq:
Struc:
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313 a.a.
277 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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Enzyme class:
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E.C.2.7.11.1
- non-specific serine/threonine protein kinase.
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Reaction:
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1.
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L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H+
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2.
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L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H+
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L-seryl-[protein]
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+
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ATP
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=
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O-phospho-L-seryl-[protein]
Bound ligand (Het Group name = )
matches with 81.25% similarity
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+
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ADP
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+
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H(+)
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L-threonyl-[protein]
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+
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ATP
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=
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O-phospho-L-threonyl-[protein]
Bound ligand (Het Group name = )
matches with 81.25% similarity
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+
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ADP
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+
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H(+)
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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J Biol Chem
280:6130-6137
(2005)
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PubMed id:
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Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase.
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K.C.Qian,
L.Wang,
E.R.Hickey,
J.Studts,
K.Barringer,
C.Peng,
A.Kronkaitis,
J.Li,
A.White,
S.Mische,
B.Farmer.
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ABSTRACT
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Pim-1 kinase is a member of a distinct class of serine/threonine kinases
consisting of Pim-1, Pim-2, and Pim-3. Pim kinases are highly homologous to one
another and share a unique consensus hinge region sequence, ER-PXPX, with its
two proline residues separated by a non-conserved residue, but they (Pim
kinases) have <30% sequence identity with other kinases. Pim-1 has been
implicated in both cytokine-induced signal transduction and the development of
lymphoid malignancies. We have determined the crystal structures of apo Pim-1
kinase and its AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) complex to
2.1-angstroms resolutions. The structures reveal the following. 1) The kinase
adopts a constitutively active conformation, and extensive hydrophobic and
hydrogen bond interactions between the activation loop and the catalytic loop
might be the structural basis for maintaining such a conformation. 2) The hinge
region has a novel architecture and hydrogen-bonding pattern, which not only
expand the ATP pocket but also serve to establish unambiguously the alignment of
the Pim-1 hinge region with that of other kinases. 3) The binding mode of
AMP-PNP to Pim-1 kinase is unique and does not involve a critical hinge region
hydrogen bond interaction. Analysis of the reported Pim-1 kinase-domain
structures leads to a hypothesis as to how Pim kinase activity might be
regulated in vivo.
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Selected figure(s)
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Figure 1.
FIG. 1. Pim-1 adopts a typical kinase fold. a, ribbon
diagram of apo Pim-1 kinase crystal structure produced using
Ribbons (35). The secondary structure  -helix and  -strand
are labeled following the conventions of the literature. The
H1-
and H2-strands are unique to
Pim-1 kinase structure and are so named for their helical
structure in cAPK. The shaded area represents the ATP binding
pocket with the active site residues shown and labeled with
single letter amino acid abbreviations and position numbers. b,
an overlay of Pim-1 and PhK using catalytic loops (produced
using Quanta). The active site residues that bind or catalyze
ATP were shown and and labeled (with single letter amino acid
abbreviations and position numbers) on the C trace of selected
regions.
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Figure 4.
FIG. 4. The atoms are colored as gray, blue, red, and
yellow for carbon, nitrogen, oxygen, and phosphor, respectively
and panels a and b were produced using Quanta. a, stereo view of
electron density (2F[o] - F[c] coefficients, 1.0  level)
for AMP-PNP with two bound magnesium ions. b, the binding
interactions of AMP-PNP phosphates with Pim-1. Lys169 does not
bind AMP-PNP in Pim-1, contrasting with what is observed in
other kinases. Single letter amino acid abbreviations are used
with position numbers.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2005,
280,
6130-6137)
copyright 2005.
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Figures were
selected
by an automated process.
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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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D.Xu,
S.A.Allsop,
S.M.Witherspoon,
J.L.Snider,
J.J.Yeh,
J.J.Fiordalisi,
C.D.White,
D.Williams,
A.D.Cox,
and
A.T.Baines
(2011).
The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells.
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Carcinogenesis,
32,
488-495.
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M.C.Nawijn,
A.Alendar,
and
A.Berns
(2011).
For better or for worse: the role of Pim oncogenes in tumorigenesis.
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Nat Rev Cancer,
11,
23-34.
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Y.Xiang,
B.Hirth,
G.Asmussen,
H.P.Biemann,
K.A.Bishop,
A.Good,
M.Fitzgerald,
T.Gladysheva,
A.Jain,
K.Jancsics,
J.Liu,
M.Metz,
A.Papoulis,
R.Skerlj,
J.D.Stepp,
and
R.R.Wei
(2011).
The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.
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Bioorg Med Chem Lett,
21,
3050-3056.
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PDB codes:
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G.Vlacich,
M.C.Nawijn,
G.C.Webb,
and
D.F.Steiner
(2010).
Pim3 negatively regulates glucose-stimulated insulin secretion.
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Islets,
2,
308-317.
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J.Kim,
M.Roh,
and
S.A.Abdulkadir
(2010).
Pim1 promotes human prostate cancer cell tumorigenicity and c-MYC transcriptional activity.
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BMC Cancer,
10,
248.
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L.Brault,
C.Gasser,
F.Bracher,
K.Huber,
S.Knapp,
and
J.Schwaller
(2010).
PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers.
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Haematologica,
95,
1004-1015.
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L.Kong,
P.V.Lovell,
A.Heger,
C.V.Mello,
and
C.P.Ponting
(2010).
Accelerated evolution of PAK3- and PIM1-like kinase gene families in the zebra finch, Taeniopygia guttata.
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Mol Biol Evol,
27,
1923-1934.
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M.Willert,
A.Augstein,
D.M.Poitz,
A.Schmeisser,
R.H.Strasser,
and
R.C.Braun-Dullaeus
(2010).
Transcriptional regulation of Pim-1 kinase in vascular smooth muscle cells and its role for proliferation.
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Basic Res Cardiol,
105,
267-277.
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N.M.Santio,
R.L.Vahakoski,
E.M.Rainio,
J.A.Sandholm,
S.S.Virtanen,
M.Prudhomme,
F.Anizon,
P.Moreau,
and
P.J.Koskinen
(2010).
Pim-selective inhibitor DHPCC-9 reveals Pim kinases as potent stimulators of cancer cell migration and invasion.
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Mol Cancer,
9,
279.
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N.S.Magnuson,
Z.Wang,
G.Ding,
and
R.Reeves
(2010).
Why target PIM1 for cancer diagnosis and treatment?
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Future Oncol,
6,
1461-1478.
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Y.Wu,
Y.Y.Wang,
Y.Nakamoto,
Y.Y.Li,
T.Baba,
S.Kaneko,
C.Fujii,
and
N.Mukaida
(2010).
Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver.
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Oncogene,
29,
2228-2237.
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A.N.Bullock,
S.Russo,
A.Amos,
N.Pagano,
H.Bregman,
J.E.Debreczeni,
W.H.Lee,
F.von Delft,
E.Meggers,
and
S.Knapp
(2009).
Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor.
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PLoS One,
4,
e7112.
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PDB code:
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J.Chen,
M.Kobayashi,
S.Darmanin,
Y.Qiao,
C.Gully,
R.Zhao,
S.C.Yeung,
and
M.H.Lee
(2009).
Pim-1 plays a pivotal role in hypoxia-induced chemoresistance.
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Oncogene,
28,
2581-2592.
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K.Peltola,
M.Hollmen,
S.M.Maula,
E.Rainio,
R.Ristamäki,
M.Luukkaa,
J.Sandholm,
M.Sundvall,
K.Elenius,
P.J.Koskinen,
R.Grenman,
and
S.Jalkanen
(2009).
Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor.
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Neoplasia,
11,
629-636.
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Y.Y.Li,
Y.Wu,
K.Tsuneyama,
T.Baba,
and
N.Mukaida
(2009).
Essential contribution of Ets-1 to constitutive Pim-3 expression in human pancreatic cancer cells.
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Cancer Sci,
100,
396-404.
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T.L.Davis,
J.R.Walker,
P.Loppnau,
C.Butler-Cole,
A.Allali-Hassani,
and
S.Dhe-Paganon
(2008).
Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3).
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Structure,
16,
873-884.
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PDB codes:
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B.K.Popivanova,
Y.Y.Li,
H.Zheng,
K.Omura,
C.Fujii,
K.Tsuneyama,
and
N.Mukaida
(2007).
Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis.
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Cancer Sci,
98,
321-328.
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J.D.Knight,
B.Qian,
D.Baker,
and
R.Kothary
(2007).
Conservation, variability and the modeling of active protein kinases.
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PLoS ONE,
2,
e982.
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J.Ma,
H.K.Arnold,
M.B.Lilly,
R.C.Sears,
and
A.S.Kraft
(2007).
Negative regulation of Pim-1 protein kinase levels by the B56beta subunit of PP2A.
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Oncogene,
26,
5145-5153.
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N.Kannan,
S.S.Taylor,
Y.Zhai,
J.C.Venter,
and
G.Manning
(2007).
Structural and functional diversity of the microbial kinome.
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PLoS Biol,
5,
e17.
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C.J.Fox,
P.S.Hammerman,
and
C.B.Thompson
(2005).
Fuel feeds function: energy metabolism and the T-cell response.
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Nat Rev Immunol,
5,
844-852.
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M.D.Jacobs,
J.Black,
O.Futer,
L.Swenson,
B.Hare,
M.Fleming,
and
K.Saxena
(2005).
Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002.
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J Biol Chem,
280,
13728-13734.
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PDB codes:
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R.Amaravadi,
and
C.B.Thompson
(2005).
The survival kinases Akt and Pim as potential pharmacological targets.
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J Clin Invest,
115,
2618-2624.
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T.L.Aho,
R.J.Lund,
E.K.Ylikoski,
S.Matikainen,
R.Lahesmaa,
and
P.J.Koskinen
(2005).
Expression of human pim family genes is selectively up-regulated by cytokines promoting T helper type 1, but not T helper type 2, cell differentiation.
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Immunology,
116,
82-88.
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Z.Wang,
M.Weaver,
and
N.S.Magnuson
(2005).
Cryptic promoter activity in the DNA sequence corresponding to the pim-1 5'-UTR.
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Nucleic Acids Res,
33,
2248-2258.
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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
