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From Proteopedia
Structure of Chlamydia trachomatis effector protein Cdu1 bound to ubiquitin
Structural highlights
FunctionCDUB1_CHLT2 Effector proteins function to alter host cell physiology and promote bacterial survival in host tissues. This protease possesses deubiquitinating and deneddylating activities (By similarity). Impairs ubiquitination and degradation of NF-kappa-B inhibitor alpha (NFKBIA), thereby preventing NF-kappa-B activation.[1] Publication Abstract from PubMedBased on the similarity between the active sites of the deubiquitylating and deneddylating enzyme ChlaDub1 (Cdu1) and the evolutionary related protease adenain a target-hopping approach screening on a focused set of adenain inhibitors has been pursued. The thereby identified cyano-pyrimidine based inhibitors represent the first active-site directed small molecule inhibitors for Cdu1. High-resolution crystal structures of Cdu1 in complex with two covalently bound cyano-pyrimidines as well as with its substrate ubiquitin have been obtained. These structural data were complemented by enzymatic assays and covalent docking studies to provide insight into Cdu1s substrate recognition, active site pocket flexibility and potential hotspots for ligand interaction. Combined, these data provide a strong foundation for future structure-guided medicinal chemistry optimization of this cyano-pyrimidine based scaffold towards more potent and specific Cdu1 inhibitors. Structural basis of substrate recognition and covalent inhibition of Cdu1 from Chlamydia trachomatis.,Ramirez YA, Adler T, Altmann E, Tiesmeyer C, Klemm T, Sauer F, Kathman S, Statsyuk A, Sotriffer C, Kisker C ChemMedChem. 2018 Jul 20. doi: 10.1002/cmdc.201800364. PMID:30028574[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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