4K60: Crystal Structure Of Human Chymase In Complex With Fragment 6-bromo-1, 3-dihydro-2h-indol-2-one

Citation:
Abstract
Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.
PDB ID: 4K60Download
MMDB ID: 110587
PDB Deposition Date: 2013/4/15
Updated in MMDB: 2013/07
Experimental Method:
x-ray diffraction
Resolution: 1.5  Å
Source Organism:
Similar Structures:
Biological Unit for 4K60: monomeric; determined by author and by software (PISA)
Molecular Components in 4K60
Label Count Molecule
Protein (1 molecule)
1
Chymase(Gene symbol: CMA1)
Molecule annotation
Chemicals (3 molecules)
1
1
2
1
3
1
* Click molecule labels to explore molecular sequence information.

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