9V5W

PfDXR - Mn2+ - SHOK317 ternary complex

This is a non-PDB format compatible entry.

Summary for 9V5W

• Entry DOI: 10.2210/pdb9v5w/pdb
• Descriptor: 1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplastic, MANGANESE (II) ION, [(1~{S})-4-[3-[1,3-bis(oxidanylidene)isoindol-2-yl]propyl-oxidanyl-amino]-4-oxidanylidene-1-phenyl-butyl]phosphonic acid, ... (6 entities in total)
• Functional Keywords: inhibitor, malaria, isomerase
• Biological source: Plasmodium falciparum HB3
• Total number of polymer chains: 2
• Total formula weight: 112966.30

Authors

Takada, S.,Sakamoto, Y.,Tanaka, N. (deposition date: 2025-05-26, release date: 2026-05-06, Last modification date: 2026-06-10)

Primary citation

Hofmann, S.,Takada, S.,Illarionov, B.,de Carvalho, L.P.,Ozawa, S.I.,Gangnus, T.,Knak, T.,Abdullaziz, M.A.,Wladarz, N.,Bacher, A.,Sakamoto, Y.,Burckhardt, B.B.,Held, J.,Fischer, M.,Tanaka, N.,Kurz, T.
Reverse Fosmidomycin Analogs as Bisubstrate Inhibitors: Binding Mode Elucidation and Mechanistic Insights.
J.Med.Chem., 69:11844-11871, 2026

PubMed Abstract: Inhibitors of the 1-deoxy--xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the nonmevalonate pathway, represent a promising class of antiplasmodial compounds, as DXR is essential for human pathogens but absent in their host. The natural product fosmidomycin was the first clinical DXR inhibitor, however high rates of recrudescence attributed to the polar phosphonic acid group have prevented progression beyond phase II clinical trials. Herein, lipophilic -benzamidoalkyl and -phthalimidoalkyl substituents were introduced into reverse α-phenyl fosmidomycin derivatives to mimic the nicotinamide moiety of the NADPH cofactor and enhance antiplasmodial activity. Elongation of the alkyl linker markedly improved enzymatic inhibition ( DXR IC = 4.3 nM) and antiplasmodial activity ( Dd2 IC = 0.28 μM). Mode of inhibition studies showed competitive inhibition with the DXR substrate and the cofactor NADPH ( K = 0.068 μM). Co-crystallization with the DXR enzyme revealed that the introduced residues bind within the NADPH binding site.

PubMed: 42089510
DOI: 10.1021/acs.jmedchem.5c03192

Experimental method

X-RAY DIFFRACTION (1.67 Å)