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* Residue conservation analysis
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DOI no:
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Protein Sci
10:1124-1129
(2001)
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PubMed id:
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High-resolution crystal structure of apolipoprotein(a) kringle IV type 7: insights into ligand binding.
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Q.Ye,
M.N.Rahman,
M.L.Koschinsky,
Z.Jia.
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ABSTRACT
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consists of a series of tandemly repeated modules
known as kringles that are commonly found in many proteins involved in the
fibrinolytic and coagulation cascades, such as plasminogen and thrombin,
respectively. Specifically, apo(a) contains multiple tandem repeats of domains
similar to plasminogen kringle IV (designated as KIV(1) to KIV(10)) followed by
sequences similar to the kringle V and protease domains of plasminogen. The KIV
domains of apo(a) differ with respect to their ability to bind lysine or lysine
analogs. KIV(10) represents the high-affinity lysine-binding site (LBS) of
apo(a); a weak LBS is predicted in each of KIV(5)-KIV(8) and has been directly
demonstrated in KIV(7). The present study describes the first crystal structure
of apo(a) KIV(7), refined to a resolution of 1.45 A, representing the highest
resolution for a kringle structure determined to date. A critical substitution
of Tyr-62 in KIV(7) for the corresponding Phe-62 residue in KIV(10), in
conjunction with the presence of Arg-35 in KIV(7), results in the formation of a
unique network of hydrogen bonds and electrostatic interactions between key LBS
residues (Arg-35, Tyr-62, Asp-54) and a peripheral tyrosine residue (Tyr-40).
These interactions restrain the flexibility of key LBS residues (Arg-35, Asp-54)
and, in turn, reduce their adaptability in accommodating lysine and its analogs.
Steric hindrance involving Tyr-62, as well as the elimination of critical
ligand-stabilizing interactions within the LBS are also consequences of this
interaction network. Thus, these subtle yet critical structural features are
responsible for the weak lysine-binding affinity exhibited by KIV(7) relative to
that of KIV(10).
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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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C.G.Earnhart,
D.V.Leblanc,
K.E.Alix,
D.C.Desrosiers,
J.D.Radolf,
and
R.T.Marconi
(2010).
Identification of residues within ligand-binding domain 1 (LBD1) of the Borrelia burgdorferi OspC protein required for function in the mammalian environment.
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Mol Microbiol, 76,
393-408.
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J.H.Geiger,
and
S.E.Cnudde
(2004).
What the structure of angiostatin may tell us about its mechanism of action.
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J Thromb Haemost, 2,
23-34.
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M.L.Koschinsky,
and
S.M.Marcovina
(2004).
Structure-function relationships in apolipoprotein(a): insights into lipoprotein(a) assembly and pathogenicity.
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Curr Opin Lipidol, 15,
167-174.
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S.P.McCormick
(2004).
Lipoprotein(a): Biology and Clinical Importance.
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Clin Biochem Rev, 25,
69-80.
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N.R.Caterer,
J.H.Graversen,
C.Jacobsen,
S.K.Moestrup,
B.W.Sigurskjold,
M.Etzerodt,
and
H.C.Thøgersen
(2002).
Specificity determinants in the interaction of apolipoprotein(a) kringles with tetranectin and LDL.
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Biol Chem, 383,
1743-1750.
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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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Links
