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PDBsum entry 2hvx
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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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Discovery of potent, orally active, nonpeptide inhibitors of human mast cell chymase by using structure-based drug design
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Structure:
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Chymase. Chain: a. Synonym: mast cell protease i. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Cell: mast cells. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108
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Resolution:
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2.60Å
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R-factor:
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0.229
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R-free:
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0.274
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Authors:
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M.N.Greco,M.J.Hawkins,E.T.Powell,H.R.Almond,L.De Garavilla,Y.Wang, L.A.Minor,G.I.Wells,E.Di Cera,A.M.Cantwell,S.N.Savvides,B.P.Damiano, B.E.Maryanoff
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Key ref:
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M.N.Greco
et al.
(2007).
Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
J Med Chem,
50,
1727-1730.
PubMed id:
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Date:
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31-Jul-06
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Release date:
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12-Jun-07
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PROCHECK
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Headers
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References
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P23946
(CMA1_HUMAN) -
Chymase from Homo sapiens
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Seq:
Struc:
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247 a.a.
226 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 3 residue positions (black
crosses)
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Enzyme class:
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E.C.3.4.21.39
- chymase.
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Reaction:
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Preferential cleavage: Phe-|-Xaa > Tyr-|-Xaa > Trp-|-Xaa > Leu-|-Xaa.
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J Med Chem
50:1727-1730
(2007)
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PubMed id:
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Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
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M.N.Greco,
M.J.Hawkins,
E.T.Powell,
H.R.Almond,
L.de Garavilla,
J.Hall,
L.K.Minor,
Y.Wang,
T.W.Corcoran,
E.Di Cera,
A.M.Cantwell,
S.N.Savvides,
B.P.Damiano,
B.E.Maryanoff.
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ABSTRACT
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A series of beta-carboxamido-phosphon(in)ic acids (2) was identified as a new
structural motif for obtaining potent inhibitors of human mast cell chymase. For
example, 1-naphthyl derivative 5f had an IC50 value of 29 nM and (E)-styryl
derivative 6g had an IC50 value of 3.5 nM. An X-ray structure for 5f.chymase
revealed key interactions within the enzyme active site. Compound 5f was
selective for inhibiting chymase versus eight serine proteases. Compound 6h was
orally bioavailable in rats (F=39%), and orally efficacious in a hamster model
of inflammation.
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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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G.H.Caughey,
J.Beauchamp,
D.Schlatter,
W.W.Raymond,
N.N.Trivedi,
D.Banner,
H.Mauser,
and
J.Fingerle
(2008).
Guinea pig chymase is leucine-specific: a novel example of functional plasticity in the chymase/granzyme family of serine peptidases.
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J Biol Chem,
283,
13943-13951.
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J.Kervinen,
M.Abad,
C.Crysler,
M.Kolpak,
A.D.Mahan,
J.A.Masucci,
S.Bayoumy,
M.D.Cummings,
X.Yao,
M.Olson,
L.de Garavilla,
L.Kuo,
I.Deckman,
and
J.Spurlino
(2008).
Structural basis for elastolytic substrate specificity in rodent alpha-chymases.
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J Biol Chem,
283,
427-436.
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PDB code:
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S.M.Belkowski,
J.Masucci,
A.Mahan,
J.Kervinen,
M.Olson,
L.de Garavilla,
and
M.R.D'Andrea
(2008).
Cleaved SLPI, a novel biomarker of chymase activity.
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Biol Chem,
389,
1219-1224.
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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
