5ETV

S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.72 angstrom resolution

Summary for 5ETV

• Entry DOI: 10.2210/pdb5etv/pdb
• Related: 5ETK 5ETL 5ETM 5ETN 5ETO 5ETP 5ETQ 5ETR 5ETS 5ETV
• Descriptor: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, 2-azanyl-8-[2-(4-bromophenyl)-2-oxidanylidene-ethyl]sulfanyl-1,9-dihydropurin-6-one, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, ampcpp, pyrophosphokinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 19316.14

Authors

Dennis, M.L.,Peat, T.S.,Swarbrick, J.D. (deposition date: 2015-11-18, release date: 2016-05-04, Last modification date: 2024-11-20)

Primary citation

Dennis, M.L.,Pitcher, N.P.,Lee, M.D.,DeBono, A.J.,Wang, Z.C.,Harjani, J.R.,Rahmani, R.,Cleary, B.,Peat, T.S.,Baell, J.B.,Swarbrick, J.D.
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, 2016

PubMed 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.

PubMed: 27094768
DOI: 10.1021/acs.jmedchem.6b00002

Experimental method

X-RAY DIFFRACTION (1.72 Å)