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PDBsum entry 2vio
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Contents |
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* Residue conservation analysis
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PDB id:
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Hydrolase
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Title:
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Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator
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Structure:
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Urokinase-type plasminogen activator chain b. Chain: a. Fragment: catalytic domain, residues 179-431. Synonym: urokinase-type plasminogen activator, upa, u-plasminogen activator. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.80Å
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R-factor:
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0.192
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R-free:
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0.250
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Authors:
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M.Frederickson,O.Callaghan,G.Chessari,M.Congreve,S.R.Cowan, J.E.Matthews,R.Mcmenamin,D.Smith,M.Vinkovic,N.G.Wallis
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Key ref:
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M.Frederickson
et al.
(2008).
Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.
J Med Chem,
51,
183-186.
PubMed id:
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Date:
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05-Dec-07
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Release date:
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22-Jan-08
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PROCHECK
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Headers
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References
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P00749
(UROK_HUMAN) -
Urokinase-type plasminogen activator from Homo sapiens
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Seq:
Struc:
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431 a.a.
248 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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*
PDB and UniProt seqs differ
at 1 residue position (black
cross)
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Enzyme class:
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E.C.3.4.21.73
- u-plasminogen activator.
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Reaction:
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Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.
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J Med Chem
51:183-186
(2008)
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PubMed id:
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Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.
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M.Frederickson,
O.Callaghan,
G.Chessari,
M.Congreve,
S.R.Cowan,
J.E.Matthews,
R.McMenamin,
D.M.Smith,
M.Vinković,
N.G.Wallis.
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ABSTRACT
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Fragment-based lead discovery has been applied to urokinase-type plasminogen
activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a
fragment hit from X-ray crystallographic screening) was the chemical starting
point. Structure-aided design led to elaborated inhibitors that retained the key
interactions of (R)-5 while gaining extra potency by simultaneously occupying
neighboring regions of the active site. Subsequent optimization led to 15, a
potent, selective, and orally bioavailable inhibitor of uPA.
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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.W.Murray,
and
T.L.Blundell
(2010).
Structural biology in fragment-based drug design.
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Curr Opin Struct Biol,
20,
497-507.
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G.E.de Kloe,
D.Bailey,
R.Leurs,
and
I.J.de Esch
(2009).
Transforming fragments into candidates: small becomes big in medicinal chemistry.
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Drug Discov Today,
14,
630-646.
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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
