PDBsum entry 5etl

Transferase/transferase inhibitor

PDB id: 5etl

Contents

Protein chains

155 a.a.

Ligands

ATP ×4

5RV ×4

Metals

_CA ×11

Waters ×528

PDB id:

5etl

Name:

Transferase/transferase inhibitor

Title:

E. Coli 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with ampcpp and inhibitor at 1.82 angstrom resolution

Structure:

2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase. Chain: a, b, c, d. Synonym: 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase,pppk,7, 8-dihydro-6-hydroxymethylpterin-pyrophosphokinase,hppk. Engineered: yes. Other_details: loop 3 residues 86-91 left unmodelled due to poor density.

Source:

Escherichia coli. Organism_taxid: 562. Gene: folk, b0142, jw0138. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.82Å R-factor: 0.204 R-free: 0.241

Authors:

M.L.Dennis,T.S.Peat,J.D.Swarbrick

Key ref:

M.L.Dennis et al. (2016). Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli. J Med Chem, 59, 5248-5263. PubMed id: 27094768 DOI: 10.1021/acs.jmedchem.6b00002

Date:

17-Nov-15 Release date: 04-May-16

Protein chains

P26281  (HPPK_ECOLI) -  2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase from Escherichia coli (strain K12)

Seq: 159 a.a.

Struc: 155 a.a.

Enzyme reactions

• Enzyme class: E.C.2.7.6.3 - 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase.
• Pathway: Folate Biosynthesis (late stages)
• Reaction: 6-hydroxymethyl-7,8-dihydropterin + ATP = (7,8-dihydropterin-6-yl)methyl diphosphate + AMP + H⁺

6-hydroxymethyl-7,8-dihydropterin + ATP (Bound ligand (Het Group name = ATP) corresponds exactly) = (7,8-dihydropterin-6-yl)methyl diphosphate + AMP + H(+)

• Cofactor: Mg(2+)

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

Added reference

DOI no: 10.1021/acs.jmedchem.6b00002

J Med Chem 59:5248-5263 (2016)

PubMed id: 27094768

Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli.

M.L.Dennis, N.P.Pitcher, M.D.Lee, A.J.DeBono, Z.C.Wang, J.R.Harjani, R.Rahmani, B.Cleary, T.S.Peat, J.B.Baell, J.D.Swarbrick.

ABSTRACT

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a member of the folate biosynthesis pathway found in prokaryotes and lower eukaryotes that catalyzes the pyrophosphoryl transfer from the ATP cofactor to a 6-hydroxymethyl-7,8-dihydropterin substrate. We report the chemical synthesis of a series of S-functionalized 8-mercaptoguanine (8MG) analogues as substrate site inhibitors of HPPK and quantify binding against the E. coli and S. aureus enzymes (EcHPPK and SaHPPK). The results demonstrate that analogues incorporating acetophenone-based substituents have comparable affinities for both enzymes. Preferential binding of benzyl-substituted 8MG derivatives to SaHPPK was reconciled when a cryptic pocket unique to SaHPPK was revealed by X-ray crystallography. Differential chemical shift perturbation analysis confirmed this to be a common mode of binding for this series to SaHPPK. One compound (41) displayed binding affinities of 120 nM and 1.76 μM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK.