PDBsum entry 1p4r

Transferase, hydrolase

PDB id: 1p4r

Contents

Protein chain

589 a.a. *

Ligands

AMZ ×2

354 ×2

XMP

Metals

__K ×2

Waters ×399

* Residue conservation analysis

PDB id:

1p4r

Name:

Transferase, hydrolase

Title:

Crystal structure of human atic in complex with folate-based inhibitor bw1540u88ud

Structure:

Bifunctional purine biosynthesis protein purh. Chain: a, b. Synonym: atic. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: atic cdna. Expressed in: escherichia coli. Expression_system_taxid: 562.

Biol. unit:

Dimer (from PQS)

Resolution:

2.55Å R-factor: 0.189 R-free: 0.257

Authors:

C.-G.Cheong,S.E.Greasley,P.A.Horton,G.P.Beardsley,I.A.Wilson

Key ref:

C.G.Cheong et al. (2004). 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. PubMed id: 14966129 DOI: 10.1074/jbc.M313691200

Date:

23-Apr-03 Release date: 30-Mar-04

Protein chains

P31939  (PUR9_HUMAN) -  Bifunctional purine biosynthesis protein ATIC from Homo sapiens

Seq: 592 a.a.

Struc: 589 a.a.

Enzyme reactions

• Enzyme class 2: E.C.2.1.2.3 - phosphoribosylaminoimidazolecarboxamide formyltransferase.
• Pathway: Purine Biosynthesis (late stages)
• Reaction: (6R)-10-formyltetrahydrofolate + 5-amino-1-(5-phospho-beta-D- ribosyl)imidazole-4-carboxamide = 5-formamido-1-(5-phospho-D- ribosyl)imidazole-4-carboxamide + (6S)-5,6,7,8-tetrahydrofolate

(6R)-10-formyltetrahydrofolate + 5-amino-1-(5-phospho-beta-D- ribosyl)imidazole-4-carboxamide = 5-formamido-1-(5-phospho-D- ribosyl)imidazole-4-carboxamide + (6S)-5,6,7,8-tetrahydrofolate (Bound ligand (Het Group name = XMP) corresponds exactly)

• Enzyme class 3: E.C.3.5.4.10 - Imp cyclohydrolase.

Pathway:

• Reaction: IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide

IMP + H2O = 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide (Bound ligand (Het Group name = XMP) corresponds exactly)

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1074/jbc.M313691200

J Biol Chem 279:18034-18045 (2004)

PubMed id: 14966129

Crystal structures of human bifunctional enzyme aminoimidazole-4-carboxamide ribonucleotide transformylase/IMP cyclohydrolase in complex with potent sulfonyl-containing antifolates.

C.G.Cheong, D.W.Wolan, S.E.Greasley, P.A.Horton, G.P.Beardsley, I.A.Wilson.

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.

Selected figure(s)

Figure 4.
FIG. 4. Comparison of the interactions of the AICAR Tfase active site with BW1540 and BW2315. A, schematic representation of the hydrogen bonding network and corresponding distances within the active site between AICAR, BW1540 and the AICAR Tfase residues. Interacting residues from the opposite subunit of the AICAR-bound monomer (black) are labeled in blue and indicated with a prime symbol. B, schematic representation of the hydrogen bonding network and corresponding distances within the AICAR Tfase active site with the bound AICAR and BW2315 molecules. Interacting residues from the opposite subunit of the AICAR-bound monomer (black) are labeled in blue and are indicated with a prime symbol.

Figure 5.
FIG. 5. Comparison of free and bound AICAR Tfase active sites. A, superposition of the AICAR- and antifolate-bound human AICAR Tfase active sites reveals slight translational and orientational deviations between the inhibitor molecules because of the propensity for the sulfonyl groups to be located in the oxyanion hole. The BW1540-bound structure is colored and labeled according to Fig. 3A. BW2315 carbons are colored orange with the BW2315-bound ATIC carbons and C trace colored in wheat. B, superposition of the BW1540-bound structure and the apo AICAR Tfase active sites reveals the slight conformational changes that occur upon folate binding. The BW1540-bound structure is colored and labeled according to Fig. 3A with the apo human ATIC C trace colored in wheat.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2004, 279, 18034-18045) copyright 2004.

Figures were selected by an automated process.