4UFX

Plasmodium vivax N-myristoyltransferase in complex with a pyridyl inhibitor (compound 19)

PDB DOI: https://doi.org/10.2210/pdb4UFX/pdb

Classification: TRANSFERASE
Organism(s): Plasmodium vivax
Expression System: Escherichia coli BL21(DE3)
Mutation(s): No

Deposited: 2015-03-19 Released: 2016-02-03
Deposition Author(s): Yu, Z., Brannigan, J.A., Rangachari, K., Heal, W.P., Wilkinson, A.J., Holder, A.A., Tate, E.W., Leatherbarrow, R.J.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.49 Å
R-Value Free: 0.197
R-Value Work: 0.158
R-Value Observed: 0.160

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of Pyridyl-Based Inhibitors of Plasmodium Falciparum N-Myristoyltransferase

Yu, Z., Brannigan, J.A., Rangachari, K., Heal, W.P., Wilkinson, A.J., Holder, A.A., Leatherbarrow, R.J., Tate, E.W.

(2015) Medchemcomm 6: 1767

PubMed: 26962430 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1039/c5md00242g
Primary Citation of Related Structures:
4UFV, 4UFW, 4UFX

PubMed Abstract:
N -Myristoyltransferase (NMT) represents an attractive drug target in parasitic infections such as malaria due to its genetic essentiality and amenability to inhibition by drug-like small molecules. Scaffold simplification from previously reported inhibitors containing bicyclic cores identified phenyl derivative 3 , providing a versatile platform to study the effects of substitution on the scaffold, which yielded pyridyl 19 . This molecule exhibited improved enzyme and cellular potency, and reduced lipophilicity compared to inhibitor 3 . Further structure-based inhibitor design led to the discovery of 30 , the most potent inhibitor in this series, which showed single-digit nM enzyme affinity and sub-μM anti-plasmodial activity.

Organizational Affiliation

Department of Chemistry , Imperial College London , London , SW7 2AZ , UK . Email: [email protected] ; Tel: +44 (0)2075 943 752.

Macromolecule Content

Total Structure Weight: 140.18 kDa
Atom Count: 11,935
Modelled Residue Count: 1,142
Deposited Residue Count: 1,155
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
GLYCYLPEPTIDE N-TETRADECANOYLTRANSFERASE	A, B, C	385	Plasmodium vivax	Mutation(s): 0 EC: 2.3.1.97
UniProt
Find proteins for A5K1A2 (Plasmodium vivax (strain Salvador I)) Explore A5K1A2 Go to UniProtKB: A5K1A2
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	A5K1A2
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 6 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NHW Query on NHW Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain N [auth B] SDF format, chain V [auth C] MOL2 format, chain E [auth A] MOL2 format, chain N [auth B] MOL2 format, chain V [auth C] mmCIF format, chain E [auth A] mmCIF format, chain N [auth B] mmCIF format, chain V [auth C]	E [auth A], N [auth B], V [auth C]	2-oxopentadecyl-CoA C₃₆ H₆₄ N₇ O₁₇ P₃ S JKWHUJMJVNMKEF-UOCZADIYSA-J		Interactions Focus chain E [auth A] Focus chain N [auth B] Focus chain V [auth C] Interactions & Density Focus chain E [auth A] Focus chain N [auth B] Focus chain V [auth C]
80O Query on 80O Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain M [auth B] SDF format, chain U [auth C] MOL2 format, chain D [auth A] MOL2 format, chain M [auth B] MOL2 format, chain U [auth C] mmCIF format, chain D [auth A] mmCIF format, chain M [auth B] mmCIF format, chain U [auth C]	D [auth A], M [auth B], U [auth C]	N-[2-(3-methoxyphenyl)ethanimidoyl]-2-piperidin-4-yloxy-pyridine-3-carboxamide C₂₀ H₂₄ N₄ O₃ GRWVIKXCGQEZMV-UHFFFAOYSA-N		Interactions Focus chain D [auth A] Focus chain M [auth B] Focus chain U [auth C] Interactions & Density Focus chain D [auth A] Focus chain M [auth B] Focus chain U [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain O [auth B] MOL2 format, chain F [auth A] MOL2 format, chain O [auth B] mmCIF format, chain F [auth A] mmCIF format, chain O [auth B]	F [auth A], O [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Focus chain O [auth B] Interactions & Density Focus chain F [auth A] Focus chain O [auth B]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain S [auth B] SDF format, chain T [auth B] SDF format, chain Y [auth C] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain S [auth B] MOL2 format, chain T [auth B] MOL2 format, chain Y [auth C] mmCIF format, chain K [auth A] mmCIF format, chain L [auth A] mmCIF format, chain S [auth B] mmCIF format, chain T [auth B] mmCIF format, chain Y [auth C]	K [auth A], L [auth A], S [auth B], T [auth B], Y [auth C]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain K [auth A] Focus chain L [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain Y [auth C] Interactions & Density Focus chain K [auth A] Focus chain L [auth A] Focus chain S [auth B] Focus chain T [auth B] Focus chain Y [auth C]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain I [auth A] SDF format, chain J [auth A] SDF format, chain Q [auth B] SDF format, chain R [auth B] SDF format, chain X [auth C] MOL2 format, chain H [auth A] MOL2 format, chain I [auth A] MOL2 format, chain J [auth A] MOL2 format, chain Q [auth B] MOL2 format, chain R [auth B] MOL2 format, chain X [auth C] mmCIF format, chain H [auth A] mmCIF format, chain I [auth A] mmCIF format, chain J [auth A] mmCIF format, chain Q [auth B] mmCIF format, chain R [auth B] mmCIF format, chain X [auth C]	H [auth A] I [auth A] J [auth A] Q [auth B] R [auth B] H [auth A], I [auth A], J [auth A], Q [auth B], R [auth B], X [auth C]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain X [auth C] Interactions & Density Focus chain H [auth A] Focus chain I [auth A] Focus chain J [auth A] Focus chain Q [auth B] Focus chain R [auth B] Focus chain X [auth C]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain P [auth B] SDF format, chain W [auth C] MOL2 format, chain G [auth A] MOL2 format, chain P [auth B] MOL2 format, chain W [auth C] mmCIF format, chain G [auth A] mmCIF format, chain P [auth B] mmCIF format, chain W [auth C]	G [auth A], P [auth B], W [auth C]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain P [auth B] Focus chain W [auth C] Interactions & Density Focus chain G [auth A] Focus chain P [auth B] Focus chain W [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.49 Å
R-Value Free: 0.197
R-Value Work: 0.158
R-Value Observed: 0.160
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 57.328	α = 90
b = 118.891	β = 90
c = 174.895	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
SCALA	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2016-02-03

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2016-02-03
Type: Initial release
Version 1.1: 2016-04-20
Changes: Database references
Version 1.2: 2024-05-08
Changes: Data collection, Database references, Derived calculations, Other