PDBsum entry 1dr1

Oxidoreductase

PDB id: 1dr1

Contents

Protein chain

186 a.a.

Ligands

NAP

HBI

Metals

_CA

Waters ×133

References listed in PDB file

Key reference

• Title: Crystal structure of chicken liver dihydrofolate reductase complexed with NADP+ and biopterin.
• Authors: M.A.Mctigue, J.F.Davies, B.T.Kaufman, J.Kraut.
• Ref.: Biochemistry, 1992, 31, 7264-7273. [DOI no: 10.1021/bi00147a009]
• PubMed id: 1510919

Note: In the PDB file this reference is annotated as "TO BE PUBLISHED". The citation details given above were obtained from the PDBe's Unpublished References server.

Abstract

The 2.2-A crystal structure of chicken liver dihydrofolate reductase (EC 1.5.1.3, DHFR) has been solved as a ternary complex with NADP+ and biopterin (a poor substrate). The space group and unit cell are isomorphous with the previously reported structure of chicken liver DHFR complexed with NADPH and phenyltriazine [Volz, K. W., Matthews, D. A., Alden, R. A., Freer, S. T., Hansch, C., Kaufman, B. T., & Kraut, J. (1982) J. Biol. Chem. 257, 2528-2536]. The structure contains an ordered water molecule hydrogen-bonded to both hydroxyls of the biopterin dihydroxypropyl group as well as to O4 and N5 of the biopterin pteridine ring. This water molecule, not observed in previously determined DHFR structures, is positioned to complete a proposed route for proton transfer from the side-chain carboxylate of E30 to N5 of the pteridine ring. Protonation of N5 is believed to occur during the reduction of dihydropteridine substrates. The positions of the NADP+ nicotinamide and biopterin pteridine rings are quite similar to the nicotinamide and pteridine ring positions in the Escherichia coli DHFR.NADP+.folate complex [Bystroff, C., Oatley, S. J., & Kraut, J. (1990) Biochemistry 29, 3263-3277], suggesting that the reduction of biopterin and the reduction of folate occur via similar mechanisms, that the binding geometry of the nicotinamide and pteridine rings is conserved between DHFR species, and that the p-aminobenzoylglutamate moiety of folate is not required for correct positioning of the pteridine ring in ground-state ternary complexes. Instead, binding of the p-aminobenzoylglutamate moiety of folate may induce the side chain of residue 31 (tyrosine or phenylalanine) in vertebrate DHFRs to adopt a conformation in which the opening to the pteridine binding site is too narrow to allow the substrate to diffuse away rapidly. A reverse conformational change of residue 31 is proposed to be required for tetrahydrofolate release.

Secondary reference #1

• Title: Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-Deazafolate.
• Authors: J.F.Davies, T.J.Delcamp, N.J.Prendergast, V.A.Ashford, J.H.Freisheim, J.Kraut.
• Ref.: Biochemistry, 1990, 29, 9467-9479. [DOI no: 10.1021/bi00492a021]
• PubMed id: 2248959

Secondary reference #2

• Title: Refined crystal structures of escherichia coli and chicken liver dihydrofolate reductase containing bound trimethoprim.
• Authors: D.A.Matthews, J.T.Bolin, J.M.Burridge, D.J.Filman, K.W.Volz, B.T.Kaufman, C.R.Beddell, J.N.Champness, D.K.Stammers, J.Kraut.
• Ref.: J Biol Chem, 1985, 260, 381-391.
• PubMed id: 3880742

Secondary reference #3

• Title: Dihydrofolate reductase. The stereochemistry of inhibitor selectivity.
• Authors: D.A.Matthews, J.T.Bolin, J.M.Burridge, D.J.Filman, K.W.Volz, J.Kraut.
• Ref.: J Biol Chem, 1985, 260, 392-399.
• PubMed id: 3880743

Secondary reference #4

• Title: Crystal structure of avian dihydrofolate reductase containing phenyltriazine and NADPH.
• Authors: K.W.Volz, D.A.Matthews, R.A.Alden, S.T.Freer, C.Hansch, B.T.Kaufman, J.Kraut.
• Ref.: J Biol Chem, 1982, 257, 2528-2536.
• PubMed id: 7061437

Secondary reference #5

• Title: Primary structure of chicken liver dihydrofolate reductase.
• Authors: A.A.Kumar, D.T.Blankenship, B.T.Kaufman, J.H.Freisheim.
• Ref.: Biochemistry, 1980, 19, 667-678. [DOI no: 10.1021/bi00545a010]
• PubMed id: 6766736