PDBsum entry 6ecr

Oxidoreductase

PDB id: 6ecr

Contents

Protein chains

285 a.a.

Ligands

NAP ×2

ACT

Waters ×223

PDB id:

6ecr

Name:

Oxidoreductase

Title:

The human methylenetetrahydrofolate dehydrogenase/cyclohydrolase (fold) complexed with NADP

Structure:

Methylenetetrahydrofolate dehydrogenase cyclohydrolase. Chain: a, b. Synonym: c1-thf synthase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mthfd1, mthfc, mthfd. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008

Resolution:

2.20Å R-factor: 0.175 R-free: 0.219

Authors:

R.V.Bueno,A.Dawson,W.N.Hunter

Key ref:

R.Bueno et al. (2019). An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement. Acta Crystallogr F Struct Biol Commun, 75, 148-152. PubMed id: 30839287 DOI: 10.1107/S2053230X18018083

Date:

08-Aug-18 Release date: 27-Mar-19

Protein chains

P11586  (C1TC_HUMAN) -  C-1-tetrahydrofolate synthase, cytoplasmic from Homo sapiens

Seq: 935 a.a.

Struc: 285 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: E.C.1.5.1.5 - methylenetetrahydrofolate dehydrogenase (NADP(+)).
• Pathway: Folate Coenzymes
• Reaction: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP⁺ = (6R)-5,10- methenyltetrahydrofolate + NADPH

(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NAP) corresponds exactly) = (6R)-5,10- methenyltetrahydrofolate + NADPH

• Enzyme class 2: E.C.3.5.4.9 - methenyltetrahydrofolate cyclohydrolase.

Pathway:

• Reaction: (6R)-5,10-methenyltetrahydrofolate + H2O = (6R)-10-formyltetrahydrofolate + H⁺
• Enzyme class 3: E.C.6.3.4.3 - formate--tetrahydrofolate ligase.

Pathway:

• Reaction: (6S)-5,6,7,8-tetrahydrofolate + formate + ATP = (6R)-10- formyltetrahydrofolate + ADP + phosphate

(6S)-5,6,7,8-tetrahydrofolate + formate + ATP (Bound ligand (Het Group name = ACT) matches with 75.00% similarity) = (6R)-10- formyltetrahydrofolate + ADP (Bound ligand (Het Group name = NAP) matches with 56.25% similarity) + phosphate

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: 10.1107/S2053230X18018083

Acta Crystallogr F Struct Biol Commun 75:148-152 (2019)

PubMed id: 30839287

An assessment of three human methylenetetrahydrofolate dehydrogenase/cyclohydrolase-ligand complexes following further refinement.

R.Bueno, A.Dawson, W.N.Hunter.

ABSTRACT

The enzymes involved in folate metabolism are key drug targets for cell-growth modulation, and accurate crystallographic structures provide templates to be exploited for structure-based ligand design. In this context, three ternary complex structures of human methylenetetrahydrofolate dehydrogenase/cyclohydrolase have been published [Schmidt et al. (2000), Biochemistry, 39, 6325-6335] and potentially represent starting points for the development of new antifolate inhibitors. However, an inspection of the models and the deposited data revealed deficiencies and raised questions about the validity of the structures. A number of inconsistencies relating to the publication were also identified. Additional refinement was carried out with the deposited data, seeking to improve the models and to then validate the complex structures or correct the record. In one case, the inclusion of the inhibitor in the structure was supported and alterations to the model allowed details of enzyme-ligand interactions to be described that had not previously been discussed. For one weak inhibitor, the data suggested that the ligand may adopt two poses in the binding site, both with few interactions with the enzyme. In the third case, that of a potent inhibitor, inconsistencies were noted in the assignment of the chemical structure and there was no evidence to support the inclusion of the ligand in the active site.