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Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis
Author(s) -
Ramirez Yesid A.,
Adler Thomas B.,
Altmann Eva,
Klemm Theresa,
Tiesmeyer Christian,
Sauer Florian,
Kathman Stefan G.,
Statsyuk Alexander V.,
Sotriffer Christoph,
Kisker Caroline
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800364
Subject(s) - active site , chemistry , covalent bond , structural similarity , docking (animal) , small molecule , hydrolase , computational biology , ligand (biochemistry) , binding site , stereochemistry , enzyme , combinatorial chemistry , biology , biochemistry , receptor , medicine , nursing , organic chemistry
Based on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionarily related protease adenain, a target‐hopping screening approach on a focused set of adenain inhibitors was investigated. The cyanopyrimidine‐based inhibitors identified represent the first active‐site‐directed small‐molecule inhibitors of Cdu1. High‐resolution crystal structures of Cdu1 in complex with two covalently bound cyanopyrimidines, as well as with its substrate ubiquitin, were obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into the substrate recognition of Cdu1, active‐site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong basis for future structure‐guided medicinal chemistry optimization of this cyanopyrimidine scaffold into more potent and selective Cdu1 inhibitors.