Exploring inhibitor binding at the S' subsites of cathepsin L.
We report a series of noncovalent, reversible inhibitors of cathepsin L that have been designed to explore additional binding interactions with the S' subsites. The design was based on our previously reported crystal structure that suggested the possibility of engineering increased interactions with the S' subsites ( Chowdhury et al. J. Med. Chem. 2002, 45, 5321-5329 ). A representative of these new inhibitors has been co-crystallized with mature cathepsin L, and the structure has been solved and refined at 2.2 A. The inhibitors described in this work extend farther into the S' subsites of cathepsins than any inhibitors reported in the literature thus far. These interactions appear to make use of a S3' subsite that can potentially be exploited for enhanced specificity and/or affinity.
Chowdhury
Shafinaz F
SF
Biotechnology Research Institute, National Research Council, Canada.
Joseph
Lissa
L
Kumar
S
S
Tulsidas
Shenoy Rajesh
SR
Bhat
Sathesh
S
Ziomek
Edmund
E
Ménard
Robert
R
Sivaraman
J
J
Purisima
Enrico O
EO
D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011485:Protein Binding; D055672:Static Electricity; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; D014443:Tyrosine; D010649:Phenylalanine; D001120:Arginine; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L