3UDE

Crystal structure of E. coli HPPK in complex with bisubstrate analogue inhibitor J1B

Summary for 3UDE

• Entry DOI: 10.2210/pdb3ude/pdb
• Related: 3UD5 3UDV
• Descriptor: 2-amino-4-hydroxy-6-hydroxymethyldihydropteridine pyrophosphokinase, 5'-S-[1-(2-{[(2-amino-7,7-dimethyl-4-oxo-3,4,7,8-tetrahydropteridin-6-yl)methyl]amino}ethyl)piperidin-4-yl]-5'-thioadenosine, ACETATE ION, ... (4 entities in total)
• Functional Keywords: alpha beta, kinase, atp binding, pyrophosphoryl transfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Escherichia coli
• Total number of polymer chains: 1
• Total formula weight: 18640.30

Authors

Shaw, G.,Shi, G.,Ji, X. (deposition date: 2011-10-28, release date: 2012-01-04, Last modification date: 2023-09-13)

Primary citation

Shi, G.,Shaw, G.,Liang, Y.H.,Subburaman, P.,Li, Y.,Wu, Y.,Yan, H.,Ji, X.
Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: New design with improved properties.
Bioorg.Med.Chem., 20:47-57, 2012

PubMed Abstract: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), a key enzyme in the folate biosynthetic pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin. The enzyme is essential for microorganisms, is absent from humans, and is not the target for any existing antibiotics. Therefore, HPPK is an attractive target for developing novel antimicrobial agents. Previously, we characterized the reaction trajectory of HPPK-catalyzed pyrophosphoryl transfer and synthesized a series of bisubstrate analog inhibitors of the enzyme by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups. Here, we report a new generation of bisubstrate analog inhibitors. To improve protein binding and linker properties of such inhibitors, we have replaced the pterin moiety with 7,7-dimethyl-7,8-dihydropterin and the phosphate bridge with a piperidine linked thioether. We have synthesized the new inhibitors, measured their K(d) and IC(50) values, determined their crystal structures in complex with HPPK, and established their structure-activity relationship. 6-Carboxylic acid ethyl ester-7,7-dimethyl-7,8-dihydropterin, a novel intermediate that we developed recently for easy derivatization at position 6 of 7,7-dimethyl-7,8-dihydropterin, offers a much high yield for the synthesis of bisubstrate analogs than that of previously established procedure.

PubMed: 22169600
DOI: 10.1016/j.bmc.2011.11.032

Experimental method

X-RAY DIFFRACTION (1.881 Å)