5GVP

Plasmodium vivax SHMT bound with PLP-glycine and GS654

PDB DOI: https://doi.org/10.2210/pdb5GVP/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Plasmodium vivax Sal-1
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2016-09-06 Released: 2017-07-12
Deposition Author(s): Chitnumsub, P., Jaruwat, A., Leartsakulpanich, U., Schwertz, G.
Funding Organization(s): National Science and Technology Development Agency

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.26 Å
R-Value Free: 0.311
R-Value Work: 0.250
R-Value Observed: 0.256

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures

Schwertz, G., Witschel, M.C., Rottmann, M., Bonnert, R., Leartsakulpanich, U., Chitnumsub, P., Jaruwat, A., Ittarat, W., Schafer, A., Aponte, R.A., Charman, S.A., White, K.L., Kundu, A., Sadhukhan, S., Lloyd, M., Freiberg, G.M., Srikumaran, M., Siggel, M., Zwyssig, A., Chaiyen, P., Diederich, F.

(2017) J Med Chem 60: 4840-4860

PubMed: 28537728 Search on PubMed
DOI: https://doi.org/10.1021/acs.jmedchem.7b00008
Primary Citation of Related Structures:
5GVK, 5GVL, 5GVM, 5GVN, 5GVP

PubMed Abstract:
Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t _1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

Organizational Affiliation

Laboratorium für Organische Chemie, ETH Zurich , Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland.

Macromolecule Content

Total Structure Weight: 150.27 kDa
Atom Count: 10,819
Modelled Residue Count: 1,326
Deposited Residue Count: 1,326
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Serine hydroxymethyltransferase, putative	A, B, C	442	Plasmodium vivax Sal-1	Mutation(s): 0 Gene Names: PVX_100730
UniProt
Find proteins for A5K8L9 (Plasmodium vivax (strain Salvador I)) Explore A5K8L9 Go to UniProtKB: A5K8L9
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A5K8L9
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
GCF Query on GCF Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain J [auth C] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain J [auth C] MOL2 format, chain F [auth A]	E [auth A], F [auth A], J [auth C]	3-[3-[3-[(4~{S})-6-azanyl-5-cyano-3-methyl-4-propan-2-yl-2~{H}-pyrano[2,3-c]pyrazol-4-yl]-5-(trifluoromethyl)phenyl]phenyl]propanoic acid C₂₇ H₂₅ F₃ N₄ O₃ ULXPNGMLUPLOIA-SANMLTNESA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain J [auth C] Interactions & Density Focus chain E [auth A] Focus chain F [auth A] Focus chain J [auth C]
PLG Query on PLG Download Ideal Coordinates CCD File SDF format, chain H [auth B] SDF format, chain I [auth C] SDF format, chain D [auth A] MOL2 format, chain H [auth B] MOL2 format, chain I [auth C] MOL2 format, chain D [auth A]	D [auth A], H [auth B], I [auth C]	N-GLYCINE-[3-HYDROXY-2-METHYL-5-PHOSPHONOOXYMETHYL-PYRIDIN-4-YL-METHANE] C₁₀ H₁₅ N₂ O₇ P FEVQWBMNLWUBTF-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain H [auth B] Focus chain I [auth C] Interactions & Density Focus chain D [auth A] Focus chain H [auth B] Focus chain I [auth C]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain K [auth C] MOL2 format, chain G [auth A] MOL2 format, chain K [auth C]	G [auth A], K [auth C]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain G [auth A] Focus chain K [auth C] Interactions & Density Focus chain G [auth A] Focus chain K [auth C]