1mhw
From Proteopedia
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Design of non-covalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides
Overview
A novel series of noncovalent inhibitors of cathepsin L have been designed, to mimic the mode of autoinhibition of procathepsin L. Just like the, propeptide, these peptide-based inhibitors have a reverse-binding mode, relative to a substrate and span both the S' and S subsites of the enzyme, active site. In contrast to previous studies in which even moderate, truncation of the full-length propeptide led to rapid reduction in, potency, these blocked tripeptide-sized inhibitors maintain nanomolar, potency. Moreover, these short peptides show higher selectivity (up to, 310-fold) for inhibiting cathepsin L over K versus only 2-fold selectivity, of the 96-residue propeptide of cathepsin L. A 1.9 A X-ray, crystallographic structure of the complex of cathepsin L with one of the, inhibitors confirms the designed reverse-binding mode of the inhibitor as, well as its noncovalent nature. Enzymatic analysis also shows the, inhibitors to be resistant to hydrolysis at elevated concentrations of the, enzyme. The mode of inhibition of these molecules provides a general, strategy for inhibiting other cathepsins as well as other proteases.
About this Structure
1MHW is a Protein complex structure of sequences from Homo sapiens. Active as Cathepsin L, with EC number 3.4.22.15 Full crystallographic information is available from OCA.
Reference
Design of noncovalent inhibitors of human cathepsin L. From the 96-residue proregion to optimized tripeptides., Chowdhury SF, Sivaraman J, Wang J, Devanathan G, Lachance P, Qi H, Menard R, Lefebvre J, Konishi Y, Cygler M, Sulea T, Purisima EO, J Med Chem. 2002 Nov 21;45(24):5321-9. PMID:12431059
Page seeded by OCA on Fri Feb 15 16:24:27 2008
