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[[Image:1thz.gif|left|200px]]
{{Seed}}
[[Image:1thz.png|left|200px]]


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{{STRUCTURE_1thz|  PDB=1thz  |  SCENE=  }}  
{{STRUCTURE_1thz|  PDB=1thz  |  SCENE=  }}  


'''Crystal Structure of Avian AICAR Transformylase in Complex with a Novel Inhibitor Identified by Virtual Ligand Screening'''
===Crystal Structure of Avian AICAR Transformylase in Complex with a Novel Inhibitor Identified by Virtual Ligand Screening===




==Overview==
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Aminoimidazole-4-carboxamide ribonucleotide transformylase (AICAR Tfase), one of the two folate-dependent enzymes in the de novo purine biosynthesis pathway, is a promising target for anti-neoplastic chemotherapy. Although classic antifolates, such as methotrexate, have been developed as anticancer agents, their general toxicity and drug resistance are major issues associated with their clinical use and future development. Identification of inhibitors with novel scaffolds could be an attractive alternative. We present here the crystal structure of avian AICAR Tfase complexed with the first non-folate based inhibitor identified through virtual ligand screening of the National Cancer Institute Diversity Set. The inhibitor 326203-A (2-[5-hydroxy-3-methyl-1-(2-methyl-4-sulfophenyl)-1H-pyrazol-4-ylazo]-4-su lfo-benzoic acid) displayed competitive inhibition against the natural cofactor, 10-formyl-tetrahydrofolate, with a K(i) of 7.1 mum. The crystal structure of AICAR Tfase with 326203-A at 1.8 A resolution revealed a unique binding mode compared with antifolate inhibitors. The inhibitor also accessed an additional binding pocket that is not occupied by antifolates. The sulfonate group of 326203-A appears to form the dominant interaction of the inhibitor with the proposed oxyanion hole through interaction with a helix dipole and Lys(267). An aromatic interaction with Phe(316) also likely contributes to favorable binding. Based on these structural insights, several inhibitors with improved potency were subsequently identified in the National Cancer Institute Compound Library and the Available Chemical Directory by similarity search and molecular modeling methods. These results provide further support for our combined virtual ligand screening rational design approach for the discovery of novel, non-folate-based inhibitors of AICAR Tfase.
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{{ABSTRACT_PUBMED_15355974}}


==About this Structure==
==About this Structure==
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==Reference==
==Reference==
Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening., Xu L, Li C, Olson AJ, Wilson IA, J Biol Chem. 2004 Nov 26;279(48):50555-65. Epub 2004 Sep 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15355974 15355974]
Crystal structure of avian aminoimidazole-4-carboxamide ribonucleotide transformylase in complex with a novel non-folate inhibitor identified by virtual ligand screening., Xu L, Li C, Olson AJ, Wilson IA, J Biol Chem. 2004 Nov 26;279(48):50555-65. Epub 2004 Sep 7. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15355974 15355974]
Structural insights into the avian AICAR transformylase mechanism., Wolan DW, Greasley SE, Beardsley GP, Wilson IA, Biochemistry. 2002 Dec 31;41(52):15505-13. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12501179 12501179]
Structure of avian AICAR transformylase with a multisubstrate adduct inhibitor beta-DADF identifies the folate binding site., Wolan DW, Greasley SE, Wall MJ, Benkovic SJ, Wilson IA, Biochemistry. 2003 Sep 23;42(37):10904-14. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/12974624 12974624]
Structural insights into the human and avian IMP cyclohydrolase mechanism via crystal structures with the bound XMP inhibitor., Wolan DW, Cheong CG, Greasley SE, Wilson IA, Biochemistry. 2004 Feb 10;43(5):1171-83. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14756553 14756553]
Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates., Cheong CG, Wolan DW, Greasley SE, Horton PA, Beardsley GP, Wilson IA, J Biol Chem. 2004 Apr 23;279(17):18034-45. Epub 2004 Feb 13. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14966129 14966129]
[[Category: Gallus gallus]]
[[Category: Gallus gallus]]
[[Category: Single protein]]
[[Category: Single protein]]
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[[Category: Purine biosynthesis]]
[[Category: Purine biosynthesis]]
[[Category: Virtual ligand screening]]
[[Category: Virtual ligand screening]]
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