4L6C

Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t

PDB DOI: https://doi.org/10.2210/pdb4L6C/pdb

Classification: HYDROLASE/HYDROLASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2013-06-12 Released: 2014-09-10
Deposition Author(s): Pachl, P., Brynda, J., Rezacova, P.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.80 ?
R-Value Free: 0.172
R-Value Work: 0.150
R-Value Observed: 0.151

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Ligand Structure Quality Assessment

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

Literature

Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.

Simak, O., Pachl, P., Fabry, M., Budesinsky, M., Jandusik, T., Hnizda, A., Sklenickova, R., Petrova, M., Veverka, V., Rezacova, P., Brynda, J., Rosenberg, I.

(2014) Org Biomol Chem 12: 7971-7982

PubMed: 25178098 Search on PubMed
DOI: https://doi.org/10.1039/c4ob01332h
Primary Citation of Related Structures:
4L6C, 4MWO, 4NFL

PubMed Abstract:
This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K = 6.60 μM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.

Organizational Affiliation

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic. rosenberg@uochb.cas.cz brynda@img.cas.cz.

Macromolecule Content

Total Structure Weight: 24.7 kDa
Atom Count: 1,948
Modelled Residue Count: 201
Deposited Residue Count: 202
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
5'(3')-deoxyribonucleotidase, mitochondrial	A	202	Homo sapiens	Mutation(s): 0 Gene Names: DNT2, NT5M EC: 3.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NPB1 (Homo sapiens) Explore Q9NPB1 Go to UniProtKB: Q9NPB1
PHAROS: Q9NPB1 GTEx: ENSG00000205309
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9NPB1
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 5 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
0BT Query on 0BT Download Ideal Coordinates CCD File SDF format, chain D [auth A] MOL2 format, chain D [auth A] mmCIF format, chain D [auth A]	D [auth A]	1-{2-deoxy-3,5-O-[(4-iodophenyl)(phosphono)methylidene]-beta-D-threo-pentofuranosyl}-5-methylpyrimidine-2,4(1H,3H)-dione C₁₇ H₁₈ I N₂ O₈ P CXQVVVNMWAGPGY-VMUDFCTBSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
PO4 Query on PO4 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	PHOSPHATE ION O₄ P NBIIXXVUZAFLBC-UHFFFAOYSA-K		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain I [auth A] SDF format, chain G [auth A] SDF format, chain H [auth A] SDF format, chain J [auth A] SDF format, chain K [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain I [auth A] MOL2 format, chain G [auth A] MOL2 format, chain H [auth A] MOL2 format, chain J [auth A] MOL2 format, chain K [auth A] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain I [auth A] mmCIF format, chain G [auth A] mmCIF format, chain H [auth A] mmCIF format, chain J [auth A] mmCIF format, chain K [auth A]	E [auth A] F [auth A] G [auth A] H [auth A] I [auth A] E [auth A], F [auth A], G [auth A], H [auth A], I [auth A], J [auth A], K [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions 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 K [auth A] Interactions & Density 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 K [auth A]
EDO Query on EDO Download Ideal Coordinates CCD File SDF format, chain L [auth A] SDF format, chain M [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] mmCIF format, chain L [auth A] mmCIF format, chain M [auth A]	L [auth A], M [auth A]	1,2-ETHANEDIOL C₂ H₆ O₂ LYCAIKOWRPUZTN-UHFFFAOYSA-N		Interactions Focus chain L [auth A] Focus chain M [auth A] Interactions & Density Focus chain L [auth A] Focus chain M [auth A]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain B [auth A] MOL2 format, chain B [auth A] mmCIF format, chain B [auth A]	B [auth A]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Interactions & Density Focus chain B [auth A]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.80 ?
R-Value Free: 0.172
R-Value Work: 0.150
R-Value Observed: 0.151
Space Group: P 4₃ 2₁ 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 73.81	α = 90
b = 73.81	β = 90
c = 105.51	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
MOSFLM	data reduction
SCALA	data scaling

Structure Validation

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Entry History

Deposition Data

Released Date: 2014-09-10

Deposition Author(s):

Pachl, P.

Brynda, J.

Rezacova, P.

Revision History (Full details and data files)

Version 1.0: 2014-09-10
Type: Initial release
Version 1.1: 2014-10-08
Changes: Database references
Version 1.2: 2024-02-28
Changes: Data collection, Database references, Derived calculations

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Help and Resources

4L6C

Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor pib-t

Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.

Entity ID: 1

UniProt & NIH Common Fund Data Resources

Entity Groups

Sequence Annotations

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Experimental Data

Structure Validation

Ligand Structure Quality Assessment

Deposition Data

Revision History (Full details and data files)