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96 a.a.
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254 a.a.
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151 a.a.
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* Residue conservation analysis
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PDB id:
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Blood clotting, hydrolase
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Title:
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Dissecting and designing inhibitor selectivity determinants at the s1 site using an artificial ala190 protease (ala190 upa)
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Structure:
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Coagulation factor vii. Chain: l. Fragment: light chain. Synonym: serum prothrombin conversion accelerator, eptacog alfa. Engineered: yes. Coagulation factor vii. Chain: h. Fragment: heavy chain (catalytic domain). Synonym: serum prothrombin conversion accelerator, eptacog alfa.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: f7. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: 293. Expression_system_organ: embryonic kidney. Gene: f3.
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Biol. unit:
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Trimer (from
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Resolution:
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2.05Å
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R-factor:
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0.226
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R-free:
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0.262
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Authors:
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B.A.Katz,C.Luong,J.D.Ho,J.R.Somoza,E.Gjerstad,J.Tang,S.R.Williams, E.Verner,R.L.Mackman,W.B.Young,P.A.Sprengeler,H.Chan,K.Mortara, J.W.Janc,M.E.Mcgrath
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Key ref:
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B.A.Katz
et al.
(2004).
Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).
J Mol Biol,
344,
527-547.
PubMed id:
DOI:
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Date:
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09-Sep-03
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Release date:
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21-Sep-04
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PROCHECK
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Headers
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References
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P08709
(FA7_HUMAN) -
Coagulation factor VII from Homo sapiens
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Seq:
Struc:
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466 a.a.
96 a.a.
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Enzyme class:
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Chains L, H:
E.C.3.4.21.21
- coagulation factor VIIa.
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Reaction:
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Hydrolyzes one Arg-|-Ile bond in factor X to form factor Xa.
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DOI no:
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J Mol Biol
344:527-547
(2004)
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PubMed id:
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Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).
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B.A.Katz,
C.Luong,
J.D.Ho,
J.R.Somoza,
E.Gjerstad,
J.Tang,
S.R.Williams,
E.Verner,
R.L.Mackman,
W.B.Young,
P.A.Sprengeler,
H.Chan,
K.Mortara,
J.W.Janc,
M.E.McGrath.
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ABSTRACT
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A site-directed mutant of the serine protease urokinase-type plasminogen
activator (uPA), was produced to assess the contribution of the Ser190
side-chain to the affinity and selectivity of lead uPA inhibitors in the absence
of other differences present in comparisons of natural proteases.
Crystallography and enzymology involving WT and Ala190 uPA were used to
calculate free energy binding contributions of hydrogen bonds involving the
Ser190 hydroxyl group (O(gamma)(Ser190)) responsible for the remarkable
selectivity of 6-halo-5-amidinoindole and 6-halo-5-amidinobenzimidazole
inhibitors toward uPA and against natural Ala190 protease anti-targets. Crystal
structures of uPA complexes of novel, active site-directed arylguanidine and
2-aminobenzimidazole inhibitors of WT uPA, together with associated K(i) values
for WT and Ala190 uPA, also indicate a significant role of Ser190 in the binding
of these classes of uPA inhibitors. Structures and associated K(i) values for a
lead inhibitor (CA-11) bound to uPA and to five other proteases, as well as for
other leads bound to multiple proteases, help reveal the features responsible
for the potency (K(i)=11nM) and selectivity of the remarkably small inhibitor,
CA-11. The 6-fluoro-5-amidinobenzimidzole, CA-11, is more than 1000-fold
selective against natural Ala190 protease anti-targets, and more than 100-fold
selective against other Ser190 anti-targets.
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Selected figure(s)
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Figure 2.
Figure 2. Structure and associated (|F[o]| -|F[c]|), a[c]
omit map for hepsin-CA-14, contoured at 2.5s.
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Figure 9.
Figure 9. S1 site structure of the complex of WT uPA with
the (a) 6-fluoro (CA-10) inhibitor and (b) the non-fluoro analog
(CA-06). Short hydrogen bonds at the active site are cyan.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
344,
527-547)
copyright 2004.
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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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T.M.Antalis,
M.S.Buzza,
K.M.Hodge,
J.D.Hooper,
and
S.Netzel-Arnett
(2010).
The cutting edge: membrane-anchored serine protease activities in the pericellular microenvironment.
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Biochem J,
428,
325-346.
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D.Bandyopadhyay,
and
E.L.Mehler
(2008).
Quantitative expression of protein heterogeneity: Response of amino acid side chains to their local environment.
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Proteins,
72,
646-659.
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F.F.Liu,
X.Y.Dong,
T.Wang,
and
Y.Sun
(2007).
Rational design of peptide ligand for affinity chromatography of tissue-type plasminogen activator by the combination of docking and molecular dynamics simulations.
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J Chromatogr A,
1175,
249-258.
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J.Tang,
C.L.Yu,
S.R.Williams,
E.Springman,
D.Jeffery,
P.A.Sprengeler,
A.Estevez,
J.Sampang,
W.Shrader,
J.Spencer,
W.Young,
M.McGrath,
and
B.A.Katz
(2005).
Expression, crystallization, and three-dimensional structure of the catalytic domain of human plasma kallikrein.
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J Biol Chem,
280,
41077-41089.
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PDB codes:
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M.Hansen,
T.Wind,
G.E.Blouse,
A.Christensen,
H.H.Petersen,
S.Kjelgaard,
L.Mathiasen,
T.L.Holtet,
and
P.A.Andreasen
(2005).
A urokinase-type plasminogen activator-inhibiting cyclic peptide with an unusual P2 residue and an extended protease binding surface demonstrates new modalities for enzyme inhibition.
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J Biol Chem,
280,
38424-38437.
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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
