4CRJ

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

4CRJ の概要

• エントリーDOI: 10.2210/pdb4crj/pdb
• 分子名称: 7,8-DIHYDRO-6-HYDROXYMETHYLPTERIN-PYROPHOSPHOKINASE (HPPK), DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: transferase, folate, structure-based drug design
• 由来する生物種: STAPHYLOCOCCUS AUREUS
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19251.27

構造登録者

Dennis, M.L.,Swarbrick, J.D.,Peat, T.S. (登録日: 2014-02-27, 公開日: 2015-01-28, 最終更新日: 2023-12-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2 Å)