Crystallographic structures of two bisphosphonate:1-deoxyxylulose-5-phosphate reductoisomerase complexes.
We have obtained the single-crystal X-ray crystallographic structures of the bisphosphonates [(1-isoquinolinylamino)methylene]-1,1-bisphosphonate and [[(5-chloro-2-pyridinyl)amino]methylene]-1,1-bisphosphonate, bound to the enzyme 1-deoxyxylulose-5-phosphate reductoisomerase (DXR, EC 1.1.1.267, also known as 2-C-methyl-d-erythritol-4-phosphate synthase), an important target for the development of antimalarial drugs. Our results indicate that both bisphosphonates bind into the fosmidomycin binding site. The aromatic groups are in a shallow hydrophobic pocket, and the phosphonate groups are involved in electrostatic interactions with Mg2+ or a cluster of carboxylic acid groups and lysine while the fosmidomycin phosphonate-binding site is occupied by a sulfate ion (as also observed in the DXR/NADP+ structure). The availability of these two new crystal structures opens up the possibility of the further development of bisphosphonates and related systems as DXR inhibitors and, potentially, as antiinfective agents.
Yajima
Shunsuke
S
Department of Bioscience, Tokyo University of Agriculture, Setagaya-ku, Tokyo 156-8502, Japan.
Hara
Kodai
K
Sanders
John M
JM
Yin
Fenglin
F
Ohsawa
Kanju
K
Wiesner
Jochen
J
Jomaa
Hassan
H
Oldfield
Eric
E
D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000201:enzymology; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011487:Protein Conformation
D004164:Diphosphonates; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D005578:Fosfomycin; C024640:fosmidomycin; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases