PDBsum entry 6fdq

Hydrolase

PDB id: 6fdq

Contents

Protein chains

239 a.a.

Ligands

2UQ ×2

Waters ×153

PDB id:

6fdq

Name:

Hydrolase

Title:

Structure of chlamydia trachomatis effector protein cdu1 bound to compound 5

Structure:

Deubiquitinase and deneddylase dub1. Chain: a, b. Synonym: chladub1. Engineered: yes

Source:

Chlamydia trachomatis serovar l2 (strain 434/bu / atcc vr-902b). Organism_taxid: 471472. Strain: 434/bu / atcc vr-902b. Gene: cdu1, ctl0247. Expressed in: escherichia coli 'bl21-gold(de3)plyss ag'. Expression_system_taxid: 866768

Resolution:

2.30Å R-factor: 0.232 R-free: 0.284

Authors:

Y.Ramirez,C.Kisker,E.Altmann

Key ref:

Y.A.Ramirez et al. (2018). Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis. ChemMedChem, 13, 2014-2023. PubMed id: 30028574

Date:

26-Dec-17 Release date: 15-Aug-18

Protein chains

B0B9A0  (CDUB1_CHLT2) -  Deubiquitinase and deneddylase Dub1 from Chlamydia trachomatis serovar L2 (strain ATCC VR-902B / DSM 19102 / 434/Bu)

Seq: 401 a.a.

Struc: 239 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.22.- - ?????

ChemMedChem 13:2014-2023 (2018)

PubMed id: 30028574

Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis.

Y.A.Ramirez, T.B.Adler, E.Altmann, T.Klemm, C.Tiesmeyer, F.Sauer, S.G.Kathman, A.V.Statsyuk, C.Sotriffer, C.Kisker.

ABSTRACT

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.