5ets | pdb_00005ets

S. aureus 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase complexed with AMPCPP and inhibitor at 1.95 angstrom resolution

spinqualitylabelsall models 5ets, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5ets is a 2 chain structure with sequence from "micrococcus_aureus"_(rosenbach_1884)_zopf_1885 "micrococcus aureus" (rosenbach 1884) zopf 1885. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 5RX, APC, MG, NA Related: 5etn, 5etk, 5etl, 5etm, 5eto, 5etp, 5etq, 5etr, 5ett, 5etv Gene: RK60_02090, RK67_01645, RK72_06915, RK74_04210, RK75_00240, RK80_01970, RK83_05435, RK84_03130, RK95_04415, RK96_04825, RK98_03440, RK99_07885, RL05_10010, RL06_09555, RL08_05305, TM59_02255 ("Micrococcus aureus" (Rosenbach 1884) Zopf 1885) Activity: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase, with EC number 2.7.6.3 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed 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. Structural Basis for the Selective Binding of Inhibitors to 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus and Escherichia coli.,Dennis ML, Pitcher NP, Lee MD, DeBono AJ, Wang ZC, Harjani JR, Rahmani R, Cleary B, Peat TS, Baell JB, Swarbrick JD J Med Chem. 2016 Apr 26. PMID:27094768 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also HPPK 3D structures

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