3NRR

Co-crystal structure of dihydrofolate reductase-thymidylate synthase from Babesia bovis with dUMP, Raltitrexed and NADP

PDB DOI: https://doi.org/10.2210/pdb3NRR/pdb

Classification: TRANSFERASE
Organism(s): Babesia bovis
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2010-06-30 Released: 2010-07-14
Deposition Author(s): Seattle Structural Genomics Center for Infectious Disease (SSGCID)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.236
R-Value Work: 0.194
R-Value Observed: 0.196

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.5 of the entry. See complete history.

Literature

Inhibitor-bound complexes of dihydrofolate reductase-thymidylate synthase from Babesia bovis.

Begley, D.W., Edwards, T.E., Raymond, A.C., Smith, E.R., Hartley, R.C., Abendroth, J., Sankaran, B., Lorimer, D.D., Myler, P.J., Staker, B.L., Stewart, L.J.

(2011) Acta Crystallogr Sect F Struct Biol Cryst Commun 67: 1070-1077

PubMed: 21904052 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1107/S1744309111029009
Primary Citation of Related Structures:
3I3R, 3K2H, 3NRR

PubMed Abstract:
Babesiosis is a tick-borne disease caused by eukaryotic Babesia parasites which are morphologically similar to Plasmodium falciparum, the causative agent of malaria in humans. Like Plasmodium, different species of Babesia are tuned to infect different mammalian hosts, including rats, dogs, horses and cattle. Most species of Plasmodium and Babesia possess an essential bifunctional enzyme for nucleotide synthesis and folate metabolism: dihydrofolate reductase-thymidylate synthase. Although thymidylate synthase is highly conserved across organisms, the bifunctional form of this enzyme is relatively uncommon in nature. The structural characterization of dihydrofolate reductase-thymidylate synthase in Babesia bovis, the causative agent of babesiosis in livestock cattle, is reported here. The apo state is compared with structures that contain dUMP, NADP and two different antifolate inhibitors: pemetrexed and raltitrexed. The complexes reveal modes of binding similar to that seen in drug-resistant malaria strains and point to the utility of applying structural studies with proven cancer chemotherapies towards infectious disease research.

Organizational Affiliation

Seattle Structural Genomics Center for Infectious Disease (http://www.ssgcid.org), USA. [email protected]

Macromolecule Content

Total Structure Weight: 122.17 kDa
Atom Count: 9,454
Modelled Residue Count: 1,004
Deposited Residue Count: 1,030
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Dihydrofolate reductase-thymidylate synthase	A, B	515	Babesia bovis	Mutation(s): 0 Gene Names: BBOV_II000780 EC: 2.1.1.45
UniProt
Find proteins for A7ASX7 (Babesia bovis) Explore A7ASX7 Go to UniProtKB: A7ASX7
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A7ASX7
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 7 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NAP Query on NAP Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain T [auth B] MOL2 format, chain D [auth A] MOL2 format, chain T [auth B] mmCIF format, chain D [auth A] mmCIF format, chain T [auth B]	D [auth A], T [auth B]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain D [auth A] Focus chain T [auth B] Interactions & Density Focus chain D [auth A] Focus chain T [auth B]
D16 Query on D16 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth A] SDF format, chain U [auth B] SDF format, chain W [auth B] MOL2 format, chain E [auth A] MOL2 format, chain G [auth A] MOL2 format, chain U [auth B] MOL2 format, chain W [auth B] mmCIF format, chain E [auth A] mmCIF format, chain G [auth A] mmCIF format, chain U [auth B] mmCIF format, chain W [auth B]	E [auth A], G [auth A], U [auth B], W [auth B]	TOMUDEX C₂₁ H₂₂ N₄ O₆ S IVTVGDXNLFLDRM-HNNXBMFYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth A] Focus chain U [auth B] Focus chain W [auth B] Interactions & Density Focus chain E [auth A] Focus chain G [auth A] Focus chain U [auth B] Focus chain W [auth B]
UMP Query on UMP Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain V [auth B] MOL2 format, chain F [auth A] MOL2 format, chain V [auth B] mmCIF format, chain F [auth A] mmCIF format, chain V [auth B]	F [auth A], V [auth B]	2'-DEOXYURIDINE 5'-MONOPHOSPHATE C₉ H₁₃ N₂ O₈ P JSRLJPSBLDHEIO-SHYZEUOFSA-N		Interactions Focus chain F [auth A] Focus chain V [auth B] Interactions & Density Focus chain F [auth A] Focus chain V [auth B]
PO4 Query on PO4 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]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain R [auth B] Interactions & Density Focus chain R [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain O [auth A] MOL2 format, chain O [auth A] mmCIF format, chain O [auth A]	O [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain O [auth A] Interactions & Density Focus chain O [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain H [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain N [auth A] SDF format, chain P [auth A] SDF format, chain Q [auth B] SDF format, chain X [auth B] SDF format, chain Y [auth B] SDF format, chain Z [auth B] SDF format, chain I [auth A] MOL2 format, chain AA [auth B] MOL2 format, chain H [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain N [auth A] MOL2 format, chain P [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain X [auth B] MOL2 format, chain Y [auth B] MOL2 format, chain Z [auth B] MOL2 format, chain I [auth A] mmCIF format, chain AA [auth B] mmCIF format, chain H [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A] mmCIF format, chain N [auth A] mmCIF format, chain P [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain X [auth B] mmCIF format, chain Y [auth B] mmCIF format, chain Z [auth B] mmCIF format, chain I [auth A]	AA [auth B] H [auth A] I [auth A] J [auth A] K [auth A] AA [auth B], H [auth A], I [auth A], J [auth A], K [auth A], L [auth A], M [auth A], N [auth A], P [auth A], Q [auth B], X [auth B], Y [auth B], Z [auth B]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain P [auth A] Focus chain Q [auth B] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain N [auth A] Focus chain P [auth A] Focus chain Q [auth B] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain S [auth B] MOL2 format, chain C [auth A] MOL2 format, chain S [auth B] mmCIF format, chain C [auth A] mmCIF format, chain S [auth B]	C [auth A], S [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain C [auth A] Focus chain S [auth B] Interactions & Density Focus chain C [auth A] Focus chain S [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 Å
R-Value Free: 0.236
R-Value Work: 0.194
R-Value Observed: 0.196
Space Group: P 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 51.33	α = 119.61
b = 83.83	β = 102.04
c = 83.92	γ = 90.26

Software Package:

Software Name	Purpose
DENZO	data reduction
SCALEPACK	data scaling
REFMAC	refinement
PDB_EXTRACT	data extraction
ADSC	data collection
PHASES	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-07-14

Deposition Author(s):

Seattle Structural Genomics Center for Infectious Disease (SSGCID)

Revision History (Full details and data files)

Version 1.0: 2010-07-14
Type: Initial release
Version 1.1: 2011-07-13
Changes: Version format compliance
Version 1.2: 2011-09-21
Changes: Database references
Version 1.3: 2012-10-10
Changes: Non-polymer description
Version 1.4: 2017-11-08
Changes: Refinement description
Version 1.5: 2023-09-06
Changes: Data collection, Database references, Derived calculations, Refinement description