Structure of N-myristoyltransferase with bound myristoylCoA and peptide substrate analogs.
N-myristoyltransferase (Nmt) attaches myristate to the N-terminal glycine of many important eukaryotic and viral proteins. It is a target for anti-fungal and anti-viral therapy. We have determined the structure, to 2.9 A resolution, of a ternary complex of Saccharomyces cerevisiae Nmt1p with bound myristoylCoA and peptide substrate analogs. The model reveals structural features that define the enzyme's substrate specificities and regulate the ordered binding and release of substrates and products. A novel catalytic mechanism is proposed involving deprotonation of the N-terminal ammonium of a peptide substrate by the enzyme's C-terminal backbone carboxylate.
Bhatnagar
R S
RS
Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Fütterer
K
K
Farazi
T A
TA
Korolev
S
S
Murray
C L
CL
Jackson-Machelski
E
E
Gokel
G W
GW
Gordon
J I
JI
Waksman
G
G
D000214:Acyl Coenzyme A / Q000378:metabolism*; D000217:Acyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002176:Candida albicans / Q000201:enzymology; D002384:Catalysis; D018360:Crystallography, X-Ray; D005656:Fungal Proteins / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D019814:Myristic Acid / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D011487:Protein Conformation; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins; D013329:Structure-Activity Relationship
D000214:Acyl Coenzyme A; D005656:Fungal Proteins; D007093:Imidazoles; C093953:NMT1 protein, S pombe; D009842:Oligopeptides; C104792:SC 58272; D029702:Schizosaccharomyces pombe Proteins; D019814:Myristic Acid; C040349:S-tetradecanoyl-coenzyme A; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase; D005998:Glycine