TY - JOUR
T1 - Crystal structure of a bifunctional transformylase and cyclohydrolase enzyme in purine biosynthesis
AU - Greasley, Samantha E.
AU - Horton, Patricia
AU - Ramcharan, Joseph
AU - Beardsley, G. Peter
AU - Benkovic, Stephen J.
AU - Wilson, Ian A.
N1 - Funding Information:
This work was supported in part by NIH Grants to I.A.W., S.J.B. and G.P.B. We thank X. Dai and A. Heine for help with data collection and advice during structure determination, M. Rudolph and R. Stanfield for valuable advice and assistance in computational analysis, J. Vergis and K. Bulock for helpful discussions, and the ALS staff of beamline 5.0.2 for guidance during data collection. This is publication 13714-MB from The Scripps Research Institute.
PY - 2001
Y1 - 2001
N2 - ATIC, the product of the purH gene, is a 64 kDa bifunctional enzyme that possesses the final two activities in de novo purine biosynthesis, AICAR transformylase and IMP cyclohydrolase. The crystal structure of avian ATIC has been determined to 1.75 Å resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of ∼5,000 Å2 per monomer. Each monomer is composed of two novel, separate functional domains. The N-terminal domain (up to residue 199) is responsible for the IMPCH activity, whereas the AICAR Tfase activity resides in the C-terminal domain (200-593). The active sites of the IMPCH and AICAR Tfase domains are ∼50 Å apart, with no structural evidence of a tunnel connecting the two active sites. The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation.
AB - ATIC, the product of the purH gene, is a 64 kDa bifunctional enzyme that possesses the final two activities in de novo purine biosynthesis, AICAR transformylase and IMP cyclohydrolase. The crystal structure of avian ATIC has been determined to 1.75 Å resolution by the MAD method using a Se-methionine modified enzyme. ATIC forms an intertwined dimer with an extensive interface of ∼5,000 Å2 per monomer. Each monomer is composed of two novel, separate functional domains. The N-terminal domain (up to residue 199) is responsible for the IMPCH activity, whereas the AICAR Tfase activity resides in the C-terminal domain (200-593). The active sites of the IMPCH and AICAR Tfase domains are ∼50 Å apart, with no structural evidence of a tunnel connecting the two active sites. The crystal structure of ATIC provides a framework to probe both catalytic mechanisms and to design specific inhibitors for use in cancer chemotherapy and inflammation.
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U2 - 10.1038/87555
DO - 10.1038/87555
M3 - Article
C2 - 11323713
AN - SCOPUS:0035032121
SN - 1072-8368
VL - 8
SP - 402
EP - 406
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 5
ER -
