Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors.
In this article we describe the application of structural biology methods to the discovery of novel potent inhibitors of methionine aminopeptidases. These enzymes are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. As this is one of the critical steps in protein maturation, it is very likely that inhibitors of these enzymes may prove useful as novel antibacterial agents. Involvement of crystallography at the very early stages of the inhibitor design process resulted in serendipitous discovery of a new inhibitor class, the pyrazole-diamines. Atomic-resolution structures of several inhibitors bound to the enzyme illuminate a new mode of inhibitor binding.
Evdokimov
Artem G
AG
Structural Biology Core Facility, The Procter & Gamble Pharmaceuticals, Mason, Ohio 45040, USA. artem@xtals.org
Pokross
Matthew
M
Walter
Richard L
RL
Mekel
Marlene
M
Barnett
Bobby L
BL
Amburgey
Jack
J
Seibel
William L
WL
Soper
Shari J
SJ
Djung
Jane F
JF
Fairweather
Neil
N
Diven
Conrad
C
Rastogi
Vinit
V
Grinius
Leo
L
Klanke
Charles
C
Siehnel
Richard
R
Twinem
Tracy
T
Andrews
Ryan
R
Curnow
Alan
A
D000626:Aminopeptidases / Q000737:chemistry / Q000302:isolation & purification; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001426:Bacterial Proteins / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D063208:Methionyl Aminopeptidases; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011789:Quantum Theory
D001426:Bacterial Proteins; D011480:Protease Inhibitors; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases