1W1Y

Crystal structure of S. marcescens chitinase B in complex with the cyclic dipeptide inhibitor cyclo-(L-Tyr-L-Pro) at 1.85 A resolution

Summary for 1W1Y

• Entry DOI: 10.2210/pdb1w1y/pdb
• Related: 1E15 1E6N 1E6P 1E6R 1E6Z 1GOI 1GPF 1OGB 1UR8 1UR9 1W1P 1W1T 1W1V
• Descriptor: CHITINASE B, GLYCEROL, SULFATE ION, ... (5 entities in total)
• Functional Keywords: hydrolase, glycoside hydrolase, chitinase, structure-based inhibitor design, cyclic dipeptide
• Biological source: SERRATIA MARCESCENS
• Total number of polymer chains: 2
• Total formula weight: 114155.29

Authors

Houston, D.R.,Synstad, B.,Eijsink, V.G.H.,Eggleston, I.,Van Aalten, D.M.F. (deposition date: 2004-06-24, release date: 2005-01-10, Last modification date: 2024-11-06)

Primary citation

Houston, D.R.,Synstad, B.,Eijsink, V.G.H.,Stark, M.J.,Eggleston, I.,Van Aalten, D.M.F.
Structure-Based Exploration of Cyclic Dipeptide Chitinase Inhibitors
J.Med.Chem., 47:5713-, 2004

PubMed Abstract: Family 18 chitinases play an essential role in a range of pathogens and pests. Several inhibitors are known, including the potent inhibitors argadin and allosamidin, and the structures of these in complex with chitinases have been elucidated. Recent structural analysis has revealed that CI-4 [cyclo-(L-Arg-D-Pro)] inhibits family 18 chitinases by mimicking the structure of the proposed reaction intermediate. Here we report the high-resolution structures of four new CI-4 derivatives, cyclo-(L-Arg-L-Pro), cyclo-(Gly-L-Pro), cyclo-(L-His-L-Pro), and cyclo-(L-Tyr-L-Pro), in complex with a family 18 chitinase. In addition, details of enzyme inhibition and in vivo activity against Saccharomyces cerevisiae are presented. The structures reveal that the common cyclo-(Gly-Pro) substructure is sufficient for binding, allowing modification of the side chain of the nonproline residue. This suggests that design of cyclic dipeptides with a view to increasing inhibition of family 18 chitinases should be possible through relatively accessible chemistry. The derivatives presented here in complex with chitinase B from Serratia marcescens provide further insight into the mechanism of inhibition of chitinases by cyclic dipeptides as well as providing a new scaffold for chitinase inhibitor design.

PubMed: 15509170
DOI: 10.1021/JM049940A

Experimental method

X-RAY DIFFRACTION (1.85 Å)