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4M5L

The Identification, Analysis and Structure-Based Development of Novel Inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase

Summary for 4M5L
Entry DOI10.2210/pdb4m5l/pdb
Related1HKA 1KBR 1Q0N 4M5G 4M5H 4M5I 4M5J 4M5K 4M5M 4M5N
Descriptor2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, DIPHOSPHOMETHYLPHOSPHONIC ACID ADENOSYL ESTER, CALCIUM ION, ... (6 entities in total)
Functional Keywordsfolate biosynthesis, diphosphotransferases, pterin, atp binding, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
Biological sourceEscherichia coli
Total number of polymer chains1
Total formula weight19412.89
Authors
Yun, M.,Hoagland, D.,Kumar, G.,Waddell, B.,Rock, C.O.,Lee, R.E.,White, S.W. (deposition date: 2013-08-08, release date: 2014-04-02, Last modification date: 2023-09-20)
Primary citationYun, M.K.,Hoagland, D.,Kumar, G.,Waddell, M.B.,Rock, C.O.,Lee, R.E.,White, S.W.
The identification, analysis and structure-based development of novel inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase.
Bioorg.Med.Chem., 22:2157-2165, 2014
Cited by
PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is an essential enzyme in the microbial folate biosynthetic pathway. This pathway has proven to be an excellent target for antimicrobial development, but widespread resistance to common therapeutics including the sulfa drugs has stimulated interest in HPPK as an alternative target in the pathway. A screen of a pterin-biased compound set identified several HPPK inhibitors that contain an aryl substituted 8-thioguanine scaffold, and structural analyses showed that these compounds engage the HPPK pterin-binding pocket and an induced cryptic pocket. A preliminary structure activity relationship profile was developed from biophysical and biochemical characterizations of derivative molecules. Also, a similarity search identified additional scaffolds that bind more tightly within the HPPK pterin pocket. These inhibitory scaffolds have the potential for rapid elaboration into novel lead antimicrobial agents.
PubMed: 24613625
DOI: 10.1016/j.bmc.2014.02.022
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.094 Å)
Structure validation

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