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PDBsum entry 3n7o
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References listed in PDB file
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Key reference
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Title
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Potency variation of small-Molecule chymase inhibitors across species.
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Authors
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J.Kervinen,
C.Crysler,
S.Bayoumy,
M.C.Abad,
J.Spurlino,
I.Deckman,
M.N.Greco,
B.E.Maryanoff,
L.De garavilla.
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Ref.
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Biochem Pharmacol, 2010,
80,
1033-1041.
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PubMed id
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Abstract
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Chymases (EC 3.4.21.39) are mast cell serine proteinases that are variably
expressed in different species and, in most cases, display either chymotryptic
or elastolytic substrate specificity. Given that chymase inhibitors have emerged
as potential therapeutic agents for treating various inflammatory, allergic, and
cardiovascular disorders, it is important to understand interspecies differences
of the enzymes as well as the behavior of inhibitors with them. We have
expressed chymases from humans, macaques, dogs, sheep (MCP2 and MCP3), guinea
pigs, and hamsters (HAM1 and HAM2) in baculovirus-infected insect cells. The
enzymes were purified and characterized with kinetic constants by using
chromogenic substrates. We evaluated in vitro the potency of five nonpeptide
inhibitors, originally targeted against human chymase. The inhibitors exhibited
remarkable cross-species variation of sensitivity, with the greatest potency
observed against human and macaque chymases, with K(i) values ranging from
approximately 0.4 to 72nM. Compounds were 10-fold to 300-fold less potent, and
in some instances ineffective, against chymases from the other species. The
X-ray structure of one of the potent phosphinate inhibitors, JNJ-18054478,
complexed with human chymase was solved at 1.8A resolution to further understand
the binding mode. Subtle variations in the residues in the active site that are
already known to influence chymase substrate specificity can also strongly
affect the compound potency. The results are discussed in the context of
selecting a suitable animal model to study compounds ultimately targeted for
human chymase.
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