4COH

Crystal structure of Trypanosoma cruzi CYP51 bound to the sulfonamide derivative of the 4-aminopyridyl-based inhibitor

Summary for 4COH

• Entry DOI: 10.2210/pdb4coh/pdb
• Descriptor: STEROL 14-ALPHA DEMETHYLASE, PROTOPORPHYRIN IX CONTAINING FE, 2-fluoranyl-N-[(2R)-3-(1H-indol-3-yl)-1-oxidanylidene-1-(pyridin-4-ylamino)propan-2-yl]-4-(4-thiophen-2-ylsulfonylpiperazin-1-yl)benzamide, ... (4 entities in total)
• Functional Keywords: transferase, cyp51, sterol 14-demethylase, sterol biosynthesis, chagas disease
• Biological source: TRYPANOSOMA CRUZI
• Total number of polymer chains: 2
• Total formula weight: 109698.68

Authors

Vieira, D.F.,Choi, J.Y.,Roush, W.R.,Podust, L.M. (deposition date: 2014-01-28, release date: 2014-04-02, Last modification date: 2023-12-20)

Primary citation

Vieira, D.F.,Choi, J.Y.,Roush, W.R.,Podust, L.M.
Expanding the Binding Envelope of Cyp51 Inhibitors Targeting Trypanosoma Cruzi with 4-Aminopyridyl-Based Sulfonamide Derivatives
Chembiochem, 15:1111-, 2014

PubMed Abstract: Chagas disease is a chronic infection caused by the protozoan parasite Trypanosoma cruzi, manifested in progressive cardiomyopathy and/or gastrointestinal dysfunction. Therapeutic options to prevent or treat Chagas disease are limited. CYP51, the enzyme key to the biosynthesis of eukaryotic membrane sterols, is a validated drug target in both fungi and T. cruzi. Sulfonamide derivatives of 4-aminopyridyl-based inhibitors of T. cruzi CYP51 (TcCYP51), including the sub-nanomolar compound 3, have molecular structures distinct from other validated CYP51 inhibitors. They augment the biologically relevant chemical space of molecules targeting TcCYP51. In a 2.08 Å X-ray structure, TcCYP51 is in a conformation that has been influenced by compound 3 and is distinct from the previously characterized ground-state conformation of CYP51 drug-target complexes. That the binding site was modulated in response to an incoming inhibitor for the first time characterizes TcCYP51 as a flexible target rather than a rigid template.

PubMed: 24771705
DOI: 10.1002/CBIC.201402027

Experimental method

X-RAY DIFFRACTION (2.08 Å)