PDBsum entry 4uoe

Transferase

PDB id: 4uoe

Contents

Protein chains

281 a.a.

Ligands

MTA ×3

4ZY ×3

GOL ×2

1PG

Waters ×426

PDB id:

4uoe

Name:

Transferase

Title:

Crystal structure of plasmodium falciparum spermidine synthase in complex with 5'-deoxy-5'-methylioadenosine and 4-aminomethylaniline

Structure:

Spermidine synthase. Chain: a, b, c. Fragment: residues 41-321. Engineered: yes

Source:

Plasmodium falciparum. Organism_taxid: 36329. Strain: 3d7. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.05Å R-factor: 0.201 R-free: 0.245

Authors:

J.Sprenger,J.C.Halander,B.Svensson,S.Al-Karadaghi,L.Person

Key ref:

J.Sprenger et al. (2015). Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design. Acta Crystallogr D Biol Crystallogr, 71, 484-493. PubMed id: 25760598 DOI: 10.1107/S1399004714027011

Date:

03-Jun-14 Release date: 08-Oct-14

Supersedes:

4bno

Protein chains

Q8II73  (Q8II73_PLAF7) -  Spermidine synthase from Plasmodium falciparum (isolate 3D7)

Seq: 321 a.a.

Struc: 281 a.a.

Enzyme reactions

• Enzyme class: E.C.2.5.1.16 - spermidine synthase.
• Pathway: Spermine Biosynthesis
• Reaction: S-adenosyl 3-(methylsulfanyl)propylamine + putrescine = S-methyl- 5'-thioadenosine + spermidine + H⁺

S-adenosyl 3-(methylsulfanyl)propylamine (Bound ligand (Het Group name = 4ZY) matches with 50.00% similarity) + putrescine = S-methyl- 5'-thioadenosine + spermidine (Bound ligand (Het Group name = MTA) corresponds exactly) + H(+)

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

reference

DOI no: 10.1107/S1399004714027011

Acta Crystallogr D Biol Crystallogr 71:484-493 (2015)

PubMed id: 25760598

Three-dimensional structures of Plasmodium falciparum spermidine synthase with bound inhibitors suggest new strategies for drug design.

J.Sprenger, B.Svensson, J.Hålander, J.Carey, L.Persson, S.Al-Karadaghi.

ABSTRACT

The enzymes of the polyamine-biosynthesis pathway have been proposed to be promising drug targets in the treatment of malaria. Spermidine synthase (SpdS; putrescine aminopropyltransferase) catalyzes the transfer of the aminopropyl moiety from decarboxylated S-adenosylmethionine to putrescine, leading to the formation of spermidine and 5'-methylthioadenosine (MTA). In this work, X-ray crystallography was used to examine ligand complexes of SpdS from the malaria parasite Plasmodium falciparum (PfSpdS). Five crystal structures were determined of PfSpdS in complex with MTA and the substrate putrescine, with MTA and spermidine, which was obtained as a result of the enzymatic reaction taking place within the crystals, with dcAdoMet and the inhibitor 4-methylaniline, with MTA and 4-aminomethylaniline, and with a compound predicted in earlier in silico screening to bind to the active site of the enzyme, benzimidazol-(2-yl)pentan-1-amine (BIPA). In contrast to the other inhibitors tested, the complex with BIPA was obtained without any ligand bound to the dcAdoMet-binding site of the enzyme. The complexes with the aniline compounds and BIPA revealed a new mode of ligand binding to PfSpdS. The observed binding mode of the ligands, and the interplay between the two substrate-binding sites and the flexible gatekeeper loop, can be used in the design of new approaches in the search for new inhibitors of SpdS.