7KDR

Crystal structure of Escherichia coli HPPK in complex with bisubstrate inhibitor HP-75

Summary for 7KDR

• Entry DOI: 10.2210/pdb7kdr/pdb
• Related: 7KDO
• Descriptor: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, 5'-{[(2R,4R)-1-{2-[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridine-6-carbonyl)amino]ethyl}-2-carboxypiperidin-4-yl]sulfonyl}-5'-deoxyadenosine, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: alpha beta, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Escherichia coli (strain K12)
• Total number of polymer chains: 1
• Total formula weight: 18830.84

Authors

Shaw, G.X.,Shi, G.,Ji, X. (deposition date: 2020-10-09, release date: 2020-12-02, Last modification date: 2023-10-18)

Primary citation

Shi, G.,Shaw, G.X.,Zhu, F.,Tarasov, S.G.,Ji, X.
Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: Transition state analogs for high affinity binding.
Bioorg.Med.Chem., 29:115847-115847, 2021

PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but absent in mammals; therefore, it is an attractive target for developing novel antimicrobial agents. Previously, based on our studies of the structure and mechanism of HPPK, we created first-generation bisubstrate inhibitors by linking 6-hydroxymethylpterin to adenosine through phosphate groups, and developed second-generation inhibitors by replacing the phosphate bridge with a linkage that contains a piperidine moiety. Here, we report third-generation inhibitors designed based on the piperidine-containing inhibitor, mimicking the transition state. We synthesized two such inhibitors, characterized their protein-binding and enzyme inhibition properties, and determined their crystal structures in complex with HPPK, advancing the development of such bisubstrate analog inhibitors.

PubMed: 33199204
DOI: 10.1016/j.bmc.2020.115847

Experimental method

X-RAY DIFFRACTION (1.488 Å)