5ETT: S. Aureus 6-hydroxymethyl-7,8-dihydropterin Pyrophosphokinase Complexed With Ampcpp And Inhibitor At 1.55 Angstrom Resolution

Citation:
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 muM for SaHPPK and EcHPPK, respectively, and represents a lead for the development of more potent and selective inhibitors of SaHPPK.
PDB ID: 5ETTDownload
MMDB ID: 138942
PDB Deposition Date: 2015/11/18
Updated in MMDB: 2016/06
Experimental Method:
x-ray diffraction
Resolution: 1.55  Å
Source Organism:
Similar Structures:
Biological Unit for 5ETT: monomeric; determined by author and by software (PISA)
Molecular Components in 5ETT
Label Count Molecule
Protein (1 molecule)
1
2-amino-4-hydroxy-6-hydroxymethyldihydropteridine Pyrophosphokinase
Molecule annotation
Chemicals (6 molecules)
1
1
2
1
3
2
4
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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