PDBsum entry 6a7c

Oxidoreductase

PDB id: 6a7c

Contents

Protein chain

186 a.a.

Ligands

NDP

9QO

SO4 ×3

Waters ×156

PDB id:

6a7c

Name:

Oxidoreductase

Title:

Human dihydrofolate reductase complexed with NADPH and bt1

Structure:

Dihydrofolate reductase. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dhfr. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.06Å R-factor: 0.175 R-free: 0.243

Authors:

J.Vanichtanankul,B.Tarnchompoo,P.Chitnumsub,S.Kamchonwongpaisan, Y.Yuthavong

Key ref:

B.Tarnchompoo et al. (2018). Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance. ACS Med Chem Lett, 9, 1235-1240. PubMed id: 30613332 DOI: 10.1021/acsmedchemlett.8b00389

Date:

02-Jul-18 Release date: 10-Apr-19

Protein chain

P00374  (DYR_HUMAN) -  Dihydrofolate reductase from Homo sapiens

Seq: 187 a.a.

Struc: 186 a.a.

Enzyme reactions

• Enzyme class: E.C.1.5.1.3 - dihydrofolate reductase.
• Pathway: Folate Coenzymes
• Reaction: (6S)-5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH + H⁺

(6S)-5,6,7,8-tetrahydrofolate + NADP(+) (Bound ligand (Het Group name = NDP) corresponds exactly) = 7,8-dihydrofolate + NADPH + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/acsmedchemlett.8b00389

ACS Med Chem Lett 9:1235-1240 (2018)

PubMed id: 30613332

Hybrid Inhibitors of Malarial Dihydrofolate Reductase with Dual Binding Modes That Can Forestall Resistance.

B.Tarnchompoo, P.Chitnumsub, A.Jaruwat, P.J.Shaw, J.Vanichtanankul, S.Poen, R.Rattanajak, C.Wongsombat, A.Tonsomboon, S.Decharuangsilp, T.Anukunwithaya, U.Arwon, S.Kamchonwongpaisan, Y.Yuthavong.

ABSTRACT

The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of P. falciparum through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound BT1 from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.