5SA1

PanDDA analysis group deposition -- Crystal Structure of Trypanosoma brucei Trypanothione reductase in complex with Z2856434944

PDB DOI: https://doi.org/10.2210/pdb5SA1/pdb
Deposition Group: G_1002197 (changed state) ExploreG_1002197

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE inhibitor
Organism(s): Trypanosoma brucei
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2021-05-18 Released: 2022-06-15
Deposition Author(s): Fiorillo, A., Ilari, A.
Funding Organization(s): iNEXT-Discovery, CNCCS

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.84 Å
R-Value Free: 0.232
R-Value Work: 0.192
R-Value Observed: 0.194

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Innovative Approach for a Classic Target: Fragment Screening on Trypanothione Reductase Reveals New Opportunities for Drug Design.

Fiorillo, A., Colotti, G., Exertier, C., Liuzzi, A., Seghetti, F., Salerno, A., Caciolla, J., Ilari, A.

(2022) Front Mol Biosci 9: 900882-900882

PubMed: 35860359 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.3389/fmolb.2022.900882
Primary Citation of Related Structures:
5S9S, 5S9T, 5S9U, 5S9V, 5S9W, 5S9X, 5S9Y, 5S9Z, 5SA0, 5SA1, 5SA2, 5SA3, 5SMJ

PubMed Abstract:
Trypanothione reductase (TR) is a key factor in the redox homeostasis of trypanosomatid parasites, critical for survival in the hostile oxidative environment generated by the host to fight infection. TR is considered an attractive target for the development of new trypanocidal agents as it is essential for parasite survival but has no close homolog in humans. However, the high efficiency and turnover of TR challenging targets since only potent inhibitors, with nanomolar IC50, can significantly affect parasite redox state and viability. To aid the design of effective compounds targeting TR, we performed a fragment-based crystal screening at the Diamond Light Source XChem facility using a library optimized for follow-up synthesis steps. The experiment, allowing for testing over 300 compounds, resulted in the identification of 12 new ligands binding five different sites. Interestingly, the screening revealed the existence of an allosteric pocket close to the NADPH binding site, named the "doorstop pocket" since ligands binding at this site interfere with TR activity by hampering the "opening movement" needed to allow cofactor binding. The second remarkable site, known as the Z-site, identified by the screening, is located within the large trypanothione cavity but corresponds to a region not yet exploited for inhibition. The fragments binding to this site are close to each other and have some remarkable features making them ideal for follow-up optimization as a piperazine moiety in three out of five fragments.

Organizational Affiliation

Institute of Molecular Biology and Pathology, Italian National Research Council, IBPM-CNR, Rome, Italy.

Macromolecule Content

Total Structure Weight: 109.79 kDa
Atom Count: 8,149
Modelled Residue Count: 969
Deposited Residue Count: 990
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
N(1),N(8)-bis(glutathionyl)spermidine reductase	A, B	495	Trypanosoma brucei	Mutation(s): 0 EC: 1.8.1.12
UniProt
Find proteins for Q389T8 (Trypanosoma brucei brucei (strain 927/4 GUTat10.1)) Explore Q389T8 Go to UniProtKB: Q389T8
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q389T8
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
FAD Query on FAD Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain M [auth B] MOL2 format, chain C [auth A] MOL2 format, chain M [auth B] mmCIF format, chain C [auth A] mmCIF format, chain M [auth B]	C [auth A], M [auth B]	FLAVIN-ADENINE DINUCLEOTIDE C₂₇ H₃₃ N₉ O₁₅ P₂ VWWQXMAJTJZDQX-UYBVJOGSSA-N		Interactions Focus chain C [auth A] Focus chain M [auth B] Interactions & Density Focus chain C [auth A] Focus chain M [auth B]
AWD (Subject of Investigation/LOI) Query on AWD Download Ideal Coordinates CCD File SDF format, chain K [auth A] MOL2 format, chain K [auth A] mmCIF format, chain K [auth A]	K [auth A]	~{N}-(4-fluorophenyl)-4-methyl-piperazine-1-carboxamide C₁₂ H₁₆ F N₃ O MDBPFVSVLGYVCQ-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Interactions & Density Focus chain K [auth A]
BR Query on BR Download Ideal Coordinates CCD File SDF format, chain R [auth B] MOL2 format, chain R [auth B] mmCIF format, chain R [auth B]	R [auth B]	BROMIDE ION Br CPELXLSAUQHCOX-UHFFFAOYSA-M		Interactions Focus chain R [auth B] Interactions & Density Focus chain R [auth B]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain N [auth B] SDF format, chain O [auth B] SDF format, chain P [auth B] SDF format, chain Q [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain N [auth B] MOL2 format, chain O [auth B] MOL2 format, chain P [auth B] MOL2 format, chain Q [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain N [auth B] mmCIF format, chain O [auth B] mmCIF format, chain P [auth B] mmCIF format, chain Q [auth B]	D [auth A] E [auth A] F [auth A] G [auth A] H [auth A] D [auth A], E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], N [auth B], O [auth B], P [auth B], Q [auth B]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain F [auth A] Focus chain G [auth A] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain N [auth B] Focus chain O [auth B] Focus chain P [auth B] Focus chain Q [auth B]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain S [auth B] MOL2 format, chain L [auth A] MOL2 format, chain S [auth B] mmCIF format, chain L [auth A] mmCIF format, chain S [auth B]	L [auth A], S [auth B]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Focus chain S [auth B] Interactions & Density Focus chain L [auth A] Focus chain S [auth B]