5JNL

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, LC54 and manganese

Summary for 5JNL

• Entry DOI: 10.2210/pdb5jnl/pdb
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic, {(2R)-2-{2-[hydroxy(methyl)amino]-2-oxoethyl}-5-[4-(trifluoromethyl)phenyl]pentyl}phosphonic acid, MANGANESE (II) ION, ... (6 entities in total)
• Functional Keywords: enzyme-inhibitor complex, mep pathway, isoprenoid biosynthesis, oxidoreductase
• Biological source: Plasmodium falciparum (isolate 3D7)
• Cellular location: Plastid, apicoplast : Q8IKG4
• Total number of polymer chains: 2
• Total formula weight: 98132.42

Authors

Sooriyaarachchi, S.,Bergfors, T.,Jones, T.A.,Mowbray, S.L. (deposition date: 2016-04-30, release date: 2016-08-24, Last modification date: 2024-01-10)

Primary citation

Sooriyaarachchi, S.,Chofor, R.,Risseeuw, M.D.,Bergfors, T.,Pouyez, J.,Dowd, C.S.,Maes, L.,Wouters, J.,Jones, T.A.,Van Calenbergh, S.,Mowbray, S.L.
Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with beta-Arylpropyl Analogues of Fosmidomycin.
Chemmedchem, 11:2024-2036, 2016

PubMed Abstract: Blocking the 2-C-methyl-d-erythrithol-4-phosphate pathway for isoprenoid biosynthesis offers new ways to inhibit the growth of Plasmodium spp. Fosmidomycin [(3-(N-hydroxyformamido)propyl)phosphonic acid, 1] and its acetyl homologue FR-900098 [(3-(N-hydroxyacetamido)propyl)phosphonic acid, 2] potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this biosynthetic pathway. Arylpropyl substituents were introduced at the β-position of the hydroxamate analogue of 2 to study changes in lipophilicity, as well as electronic and steric properties. The potency of several new compounds on the P. falciparum enzyme approaches that of 1 and 2. Activities against the enzyme and parasite correlate well, supporting the mode of action. Seven X-ray structures show that all of the new arylpropyl substituents displace a key tryptophan residue of the active-site flap, which had made favorable interactions with 1 and 2. Plasticity of the flap allows substituents to be accommodated in many ways; in most cases, the flap is largely disordered. Compounds can be separated into two classes based on whether the substituent on the aromatic ring is at the meta or para position. Generally, meta-substituted compounds are better inhibitors, and in both classes, smaller size is linked to better potency.

PubMed: 27487410
DOI: 10.1002/cmdc.201600249

Experimental method

X-RAY DIFFRACTION (1.6 Å)