4CRJ

Staphylococcus aureus 7,8-Dihydro-6-hydroxymethylpterin- pyrophosphokinase in complex with AMPCPP and an inhibitor

Summary for 4CRJ

• Entry DOI: 10.2210/pdb4crj/pdb
• Descriptor: 7,8-DIHYDRO-6-HYDROXYMETHYLPTERIN-PYROPHOSPHOKINASE (HPPK), DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: transferase, folate, structure-based drug design
• Biological source: STAPHYLOCOCCUS AUREUS
• Total number of polymer chains: 1
• Total formula weight: 19251.27

Authors

Dennis, M.L.,Swarbrick, J.D.,Peat, T.S. (deposition date: 2014-02-27, release date: 2015-01-28, Last modification date: 2023-12-20)

Primary citation

Dennis, M.L.,Chhabra, S.,Wang, Z.,Debono, A.,Dolezal, O.,Newman, J.,Pitcher, N.P.,Rahmani, R.,Cleary, B.,Barlow, N.,Hattarki, M.,Graham, B.,Peat, T.S.,Baell, J.B.,Swarbrick, J.D.
Structure-Based Design and Development of Functionalized Mercaptoguanine Derivatives as Inhibitors of the Folate Biosynthesis Pathway Enzyme 6-Hydroxymethyl-7,8-Dihydropterin Pyrophosphokinase from Staphylococcus Aureus.
J.Med.Chem., 57:9612-, 2014

PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 Å upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors.

PubMed: 25357262
DOI: 10.1021/JM501417F

Experimental method

X-RAY DIFFRACTION (2 Å)