4KP7

Structure of Plasmodium IspC in complex with a beta-thia-isostere derivative of Fosmidomycin

PDB DOI: https://doi.org/10.2210/pdb4KP7/pdb

Classification: oxidoreductase/oxidoreductase INHIBITOR
Organism(s): Plasmodium falciparum HB3
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2013-05-13 Released: 2013-10-02
Deposition Author(s): Kunfermann, A., Bacher, A., Groll, M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.249
R-Value Work: 0.185
R-Value Observed: 0.188

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Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

IspC as Target for Antiinfective Drug Discovery: Synthesis, Enantiomeric Separation, and Structural Biology of Fosmidomycin Thia Isosters.

Kunfermann, A., Lienau, C., Illarionov, B., Held, J., Grawert, T., Behrendt, C.T., Werner, P., Hahn, S., Eisenreich, W., Riederer, U., Mordmuller, B., Bacher, A., Fischer, M., Groll, M., Kurz, T.

(2013) J Med Chem 56: 8151-8162

PubMed: 24032981 Search on PubMed
DOI: https://doi.org/10.1021/jm4012559
Primary Citation of Related Structures:
4KP7

PubMed Abstract:
The emergence and spread of multidrug-resistant pathogens are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the synthesis and properties of "reverse" thia analogs of fosmidomycin, which inhibit the first committed enzyme of a metabolic pathway that is essential for the causative agents of tuberculosis and malaria but is absent in the human host. Notably, IspC displays a high level of enantioselectivity for an α-substituted fosmidomycin derivative.

Organizational Affiliation

Center for Integrated Protein Science Munich, Lehrstuhl für Biochemie, Technische Universität München , Lichtenbergstrasse 4, 85747 Garching, Germany.

Macromolecule Content

Total Structure Weight: 98.74 kDa
Atom Count: 6,790
Modelled Residue Count: 811
Deposited Residue Count: 854
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast	A, B	427	Plasmodium falciparum HB3	Mutation(s): 0 Gene Names: codon optimized form, DXR, synthetic EC: 1.1.1.267
UniProt
Find proteins for O96693 (Plasmodium falciparum (isolate HB3)) Explore O96693 Go to UniProtKB: O96693
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O96693
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 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] MOL2 format, chain D [auth A]	D [auth A]	NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₂₈ N₇ O₁₇ P₃ XJLXINKUBYWONI-NNYOXOHSSA-N		Interactions Focus chain D [auth A] Interactions & Density Focus chain D [auth A]
1UQ Query on 1UQ Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B]	E [auth A], G [auth B]	[(S)-({2-[hydroxy(methyl)amino]-2-oxoethyl}sulfanyl)(phenyl)methyl]phosphonic acid C₁₀ H₁₄ N O₅ P S IWQBQVIYTMIQRL-JTQLQIEISA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Interactions & Density Focus chain E [auth A] Focus chain G [auth B]
MN3 Query on MN3 Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B]	C [auth A], F [auth B]	MANGANESE (III) ION Mn MMIPFLVOWGHZQD-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
1UQ	Binding MOAD: 4KP7	IC50: 9.4 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.249
R-Value Work: 0.185
R-Value Observed: 0.188
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 51.46	α = 90
b = 78.12	β = 91.53
c = 99.99	γ = 90

Software Package:

Software Name	Purpose
XDS	data scaling
PHASER	phasing
REFMAC	refinement
XDS	data reduction
XSCALE	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-10-02

Deposition Author(s):

Kunfermann, A.

Bacher, A.

Groll, M.

Revision History (Full details and data files)

Version 1.0: 2013-10-02
Type: Initial release
Version 1.1: 2013-10-30
Changes: Database references
Version 1.2: 2014-02-12
Changes: Database references
Version 1.3: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description