6JVU

Crystal structure of Klebsiella pneumoniae CysE in complex with L-cysteine

Summary for 6JVU

• Entry DOI: 10.2210/pdb6jvu/pdb
• Descriptor: Serine acetyltransferase, 1,2-ETHANEDIOL, CYSTEINE, ... (5 entities in total)
• Functional Keywords: serine acetyltransferase, transferase
• Biological source: Klebsiella pneumoniae MGH 78578
• Total number of polymer chains: 6
• Total formula weight: 182945.21

Authors

Verma, D.,Gupta, V. (deposition date: 2019-04-17, release date: 2020-02-26, Last modification date: 2023-11-22)

Primary citation

Verma, D.,Gupta, S.,Saxena, R.,Kaur, P.,R, R.,Srivastava, S.,Gupta, V.
Allosteric inhibition and kinetic characterization of Klebsiella pneumoniae CysE: An emerging drug target.
Int.J.Biol.Macromol., 151:1240-1249, 2020

PubMed Abstract: The emergence and spread of multidrug-resistant strains of Klebsiella pneumoniae is a major concern that necessitates the development of unique therapeutics. The essential requirement of serine acetyltransferase (SAT/CysE) for survival of several human pathogens makes it a very promising target for inhibitor designing and drug discovery. In this study, as an initial step to structure-based drug discovery, CysE from K. pneumonia was structurally and biochemically characterized. Subsequently, blind docking of selected natural products into the X-ray crystallography determined 3D structure of the target was carried out. Experimental validation of the inhibitory potential of the top-scorers established quercetin as an uncompetitive inhibitor of Kpn CysE. Molecular dynamics simulations carried out to elucidate the binding mode of quercetin reveal that this small molecule binds at the trimer-trimer interface of hexameric CysE, a site physically distinct from the active site of the enzyme. Detailed analysis of conformational differences incurred in Kpn CysE structure on binding to quercetin provides mechanistic understanding of allosteric modulation. Binding of quercetin to CysE leads to conformation changes in the active site loops and proximal loops that affect its internal dynamics and consequently its affinity for substrate/co-factor binding, justifying the reduced enzyme activity.

PubMed: 31751684
DOI: 10.1016/j.ijbiomac.2019.10.170

Experimental method

X-RAY DIFFRACTION (2.8 Å)