Immucillins in custom catalytic-site cavities.
Neighboring-group participation in the reaction catalyzed by purine nucleoside phosphorylase involves a compression mode between the 5'- and 4'-ribosyl oxygens, facilitated by His257. The His257Gly mutant opens a space in the catalytic site. Hydrophobic 5'-substituted Immucillins are transition-state analogue inhibitors of this mutant enzyme. Dissociation constants as low as 2pM are achieved, with K(m)/K(d) as high as 400,000,000.
Murkin
Andrew S
AS
Department of Biochemistry, Albert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Clinch
Keith
K
Mason
Jennifer M
JM
Tyler
Peter C
PC
Schramm
Vern L
VL
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006639:Histidine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D009154:Mutation; D011487:Protein Conformation; D011684:Purine Nucleosides / Q000737:chemistry*; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000737:chemistry*; D013329:Structure-Activity Relationship
D007093:Imidazoles; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine; D006639:Histidine; D011683:Purine-Nucleoside Phosphorylase; D005998:Glycine
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