1dhf

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spinqualitylabelsall models 1dhf, resolution 2.3Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

CRYSTAL STRUCTURES OF RECOMBINANT HUMAN DIHYDROFOLATE REDUCTASE COMPLEXED WITH FOLATE AND 5-DEAZOFOLATE

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

The 2.3-A crystal structure of recombinant human dihydrofolate reductase, (EC 1.5.1.3, DHFR) has been solved as a binary complex with folate (a poor, substrate at neutral pH) and also as a binary complex with an inhibitor, 5-deazafolate. The inhibitor appears to be protonated at N8 on binding, whereas folate is not. Rotation of the peptide plane joining I7 and V8, from its position in the folate complex permits hydrogen bonding of, 5-deazafolate's protonated N8 to the backbone carbonyl of I7, thus, contributing to the enzyme's greater affinity for 5-deazafolate than for, folate. In this respect it is likely that bound 5-deazafolate furnishes a, model for 7,8-dihydrofolate binding and, in addition, resembles the, transition state for folate reduction. A hypothetical transition-state, model for folate reduction, generated by superposition of the DHFR binary, complexes human.5-deazafolate and chicken liver.NADPH, reveals a 1-A, overlap of the binding sites for folate's pteridine ring and the, dihydronicotinamide ring of NADPH. It is proposed that this binding-site, overlap accelerates the reduction of both folate and 7,8-dihydrofolate by, simultaneously binding substrate and cofactor with a sub van der Waals, separation that is optimal for hydride transfer.

Disease

Known disease associated with this structure: Anemia, megaloblastic, due to DHFR deficiency (1) OMIM:[126060]

About this Structure

1DHF is a Single protein structure of sequence from Homo sapiens with FOL as ligand. Active as Dihydrofolate reductase, with EC number 1.5.1.3 Full crystallographic information is available from OCA.

Reference

Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate., Davies JF 2nd, Delcamp TJ, Prendergast NJ, Ashford VA, Freisheim JH, Kraut J, Biochemistry. 1990 Oct 9;29(40):9467-79. PMID:2248959

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