4Z2I

Serratia marcescens Chitinase B complexed with macrolide inhibitor 30

Summary for 4Z2I

• Entry DOI: 10.2210/pdb4z2i/pdb
• Related: 3WD0 4Z2G 4Z2H 4Z2J 4Z2K 4Z2L
• Descriptor: Chitinase B, (1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,17S)-3-ethyl-2,10-dihydroxy-2,6,8,10,12,15,15,17-octamethyl-5-oxo-9-(prop-2-yn-1-yloxy)-4,14,16-trioxabicyclo[11.3.1]heptadec-7-yl {3-[N'-(methylcarbamoyl)carbamimidamido]propyl}carbamate, SODIUM ION, ... (7 entities in total)
• Functional Keywords: chitinase, inhibitor, macrolide, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Serratia marcescens
• Total number of polymer chains: 1
• Total formula weight: 57823.50

Authors

Maita, N.,Sugawara, A.,Sunazuka, T. (deposition date: 2015-03-30, release date: 2015-07-01, Last modification date: 2024-10-23)

Primary citation

Sugawara, A.,Maita, N.,Gouda, H.,Yamamoto, T.,Hirose, T.,Kimura, S.,Saito, Y.,Nakano, H.,Kasai, T.,Nakano, H.,Shiomi, K.,Hirono, S.,Watanabe, T.,Taniguchi, H.,Omura, S.,Sunazuka, T.
Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase
J.Med.Chem., 58:4984-4997, 2015

PubMed Abstract: Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits ∼200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.

PubMed: 26030312
DOI: 10.1021/acs.jmedchem.5b00175

Experimental method

X-RAY DIFFRACTION (2 Å)