Function of the D-alanine:D-alanine ligase lid loop: a molecular modeling and bioactivity study.
D-Alanine:D-alanine ligase (Ddl) is an essential ATP-dependent bacterial enzyme involved in peptidoglycan biosynthesis. Discovery of Ddl inhibitors not competitive with ATP has proven to be difficult because the Ddl bimolecular d-alanine binding pocket is very restricted, as is accessibility to the active site for larger molecules in the catalytically active closed conformation of Ddl. A molecular dynamics study of the opening and closing of the Ddl lid loop informs future structure-based design efforts that allow for the flexibility of Ddl. A virtual screen on generated enzyme conformations yielded some hit inhibitors whose bioactivity was determined.
Faculty of Pharmacy,  University of Ljubljana , Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
Martina
M
Hrast
Blaž
B
Vehar
Samo
S
Turk
Janez
J
Konc
Stanislav
S
Gobec
Dušanka
D
Janežič
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry; D057075:Enzyme Assays; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013824:Thermus / Q000201:enzymology
D001426:Bacterial Proteins; D052160:Benzothiazoles; D029968:Escherichia coli Proteins; D007555:Isoxazoles; D011719:Pyrazines; D011743:Pyrimidines; D010453:Peptide Synthases; C019638:D-alanylalanine synthetase