Structural characterization of ß-ketoacyl ACP synthase I bound to platencin and fragment screening molecules at two substrate binding sites.
Proteins
; 88(1): 47-56, 2020 01.
Article
in En
| MEDLINE
| ID: mdl-31237717
ABSTRACT
The bacterial fatty acid pathway is essential for membrane synthesis and a range of other metabolic and cellular functions. The ß-ketoacyl-ACP synthases carry out the initial elongation reaction of this pathway, utilizing acetyl-CoA as a primer to elongate malonyl-ACP by two carbons, and subsequent elongation of the fatty acyl-ACP substrate by two carbons. Here we describe the structures of the ß-ketoacyl-ACP synthase I from Brucella melitensis in complex with platencin, 7-hydroxycoumarin, and (5-thiophen-2-ylisoxazol-3-yl)methanol. The enzyme is a dimer and based on structural and sequence conservation, harbors the same active site configuration as other ß-ketoacyl-ACP synthases. The platencin binding site overlaps with the fatty acyl compound supplied by ACP, while 7-hydroxyl-coumarin and (5-thiophen-2-ylisoxazol-3-yl)methanol bind at the secondary fatty acyl binding site. These high-resolution structures, ranging between 1.25 and 1.70 å resolution, provide a basis for in silico inhibitor screening and optimization, and can aid in rational drug design by revealing the high-resolution binding interfaces of molecules at the malonyl-ACP and acyl-ACP active sites.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase
/
Polycyclic Compounds
/
Brucella melitensis
/
Enzyme Inhibitors
/
Aminophenols
Type of study:
Diagnostic_studies
/
Screening_studies
Limits:
Humans
Language:
En
Journal:
Proteins
Journal subject:
BIOQUIMICA
Year:
2020
Type:
Article