1PL0

Crystal structure of human ATIC in complex with folate-based inhibitor, BW2315U89UC

Summary for 1PL0

• Entry DOI: 10.2210/pdb1pl0/pdb
• Related: 1P4R 1PKX
• Descriptor: Bifunctional purine biosynthesis protein PURH, POTASSIUM ION, XANTHOSINE-5'-MONOPHOSPHATE, ... (6 entities in total)
• Functional Keywords: human atic, aicar, aicar transformylase, imp cyclohydrolase, xanthosine monophosphate, folate-based inhibitor, bw2315u89uc, transferase, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 261655.24

Authors

Cheong, C.G.,Greasley, S.E.,Horton, P.A.,Beardsley, G.P.,Wilson, I.A. (deposition date: 2003-06-06, release date: 2004-04-27, Last modification date: 2023-08-16)

Primary citation

Cheong, C.G.,Wolan, D.W.,Greasley, S.E.,Horton, P.A.,Beardsley, G.P.,Wilson, I.A.
Crystal Structures of Human Bifunctional Enzyme Aminoimidazole-4-carboxamide Ribonucleotide Transformylase/IMP Cyclohydrolase in Complex with Potent Sulfonyl-containing Antifolates.
J.Biol.Chem., 279:18034-18045, 2004

PubMed Abstract: Aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/IMP cyclohydrolase (ATIC) is a bifunctional enzyme with folate-dependent AICAR transformylase and IMP cyclohydrolase activities that catalyzes the last two steps of purine biosynthesis. The AICAR transformylase inhibitors BW1540 and BW2315 are sulfamido-bridged 5,8-dideazafolate analogs with remarkably potent K(i) values of 8 and 6 nm, respectively, compared with most other antifolates. Crystal structures of ATIC at 2.55 and 2.60 A with each inhibitor, in the presence of substrate AICAR, revealed that the sulfonyl groups dominate inhibitor binding and orientation through interaction with the proposed oxyanion hole. These agents then appear to mimic the anionic transition state and now implicate Asn(431') in the reaction mechanism along with previously identified key catalytic residues Lys(266) and His(267). Potent and selective inhibition of the AICAR transformylase active site, compared with other folate-dependent enzymes, should therefore be pursued by further design of sulfonyl-containing antifolates.

PubMed: 14966129
DOI: 10.1074/jbc.M313691200

Experimental method

X-RAY DIFFRACTION (2.6 Å)