4UFW

Plasmodium vivax N-myristoyltransferase in complex with a pyridyl inhibitor (compound 22)

PDB DOI: https://doi.org/10.2210/pdb4UFW/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: 1.50 ?
R-Value Free: 0.261
R-Value Work: 0.214
R-Value Observed: 0.217

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: e.tate@imperial.ac.uk ; Tel: +44 (0)2075 943 752.

Macromolecule Content

Total Structure Weight: 139.92 kDa
Atom Count: 11,389
Modelled Residue Count: 1,137
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 D [auth A] SDF format, chain J [auth B] SDF format, chain O [auth C] MOL2 format, chain D [auth A] MOL2 format, chain J [auth B] MOL2 format, chain O [auth C] mmCIF format, chain D [auth A] mmCIF format, chain J [auth B] mmCIF format, chain O [auth C]	D [auth A], J [auth B], O [auth C]	2-oxopentadecyl-CoA C₃₆ H₆₄ N₇ O₁₇ P₃ S JKWHUJMJVNMKEF-UOCZADIYSA-J		Interactions Focus chain D [auth A] Focus chain J [auth B] Focus chain O [auth C] Interactions & Density Focus chain D [auth A] Focus chain J [auth B] Focus chain O [auth C]
7Y6 Query on 7Y6 Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain K [auth B] SDF format, chain P [auth C] MOL2 format, chain E [auth A] MOL2 format, chain K [auth B] MOL2 format, chain P [auth C] mmCIF format, chain E [auth A] mmCIF format, chain K [auth B] mmCIF format, chain P [auth C]	E [auth A], K [auth B], P [auth C]	4-chloranyl-N-[2-(3-methoxyphenyl)ethanimidoyl]-2-piperidin-4-yloxy-benzamide C₂₁ H₂₄ Cl N₃ O₃ LWKDHLRBDHZTMF-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain K [auth B] Focus chain P [auth C] Interactions & Density Focus chain E [auth A] Focus chain K [auth B] Focus chain P [auth C]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain F [auth A] MOL2 format, chain F [auth A] mmCIF format, chain F [auth A]	F [auth A]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
DMS Query on DMS Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain N [auth B] SDF format, chain S [auth C] MOL2 format, chain I [auth A] MOL2 format, chain N [auth B] MOL2 format, chain S [auth C] mmCIF format, chain I [auth A] mmCIF format, chain N [auth B] mmCIF format, chain S [auth C]	I [auth A], N [auth B], S [auth C]	DIMETHYL SULFOXIDE C₂ H₆ O S IAZDPXIOMUYVGZ-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain N [auth B] Focus chain S [auth C] Interactions & Density Focus chain I [auth A] Focus chain N [auth B] Focus chain S [auth C]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain H [auth A] SDF format, chain M [auth B] SDF format, chain R [auth C] MOL2 format, chain H [auth A] MOL2 format, chain M [auth B] MOL2 format, chain R [auth C] mmCIF format, chain H [auth A] mmCIF format, chain M [auth B] mmCIF format, chain R [auth C]	H [auth A], M [auth B], R [auth C]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain H [auth A] Focus chain M [auth B] Focus chain R [auth C] Interactions & Density Focus chain H [auth A] Focus chain M [auth B] Focus chain R [auth C]
MG Query on MG Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain L [auth B] SDF format, chain Q [auth C] MOL2 format, chain G [auth A] MOL2 format, chain L [auth B] MOL2 format, chain Q [auth C] mmCIF format, chain G [auth A] mmCIF format, chain L [auth B] mmCIF format, chain Q [auth C]	G [auth A], L [auth B], Q [auth C]	MAGNESIUM ION Mg JLVVSXFLKOJNIY-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain L [auth B] Focus chain Q [auth C] Interactions & Density Focus chain G [auth A] Focus chain L [auth B] Focus chain Q [auth C]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.50 ?
R-Value Free: 0.261
R-Value Work: 0.214
R-Value Observed: 0.217
Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( ? )	Angle ( ? )
a = 57.52	α = 90
b = 121.91	β = 90
c = 178.8	γ = 90

Software Package:

Software Name	Purpose
REFMAC	refinement
XDS	data reduction
SCALA	data scaling

Structure Validation

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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

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Help and Resources

4UFW

Plasmodium vivax N-myristoyltransferase in complex with a pyridyl inhibitor (compound 22)

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

Entity ID: 1

UniProt

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)