6fdk
From Proteopedia
Structure of Chlamydia trachomatis effector protein Cdu1 bound to ubiquitin
Structural highlights
Function[CDUB1_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] [UBB_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[2] [3] 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[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Kisker, C | Ramirez, Y | Ce protease | Chladub1 | Dub | Hydrolase | Ubiquitin
