4YND | pdb_00004ynd

The Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2

PDB DOI: https://doi.org/10.2210/pdb4YND/pdb

Classification: Transferase/Inhibitor
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2015-03-09 Released: 2015-05-20
Deposition Author(s): Sweis, R.F., Wang, Z., Algire, M., Arrowsmith, C.H., Brown, P.J., Chiang, G.C., Guo, J., Jakob, C.G., Kennedy, S., Li, F., Soni, N.B., Vedadi, M., Pappano, W.N.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.79 Å
R-Value Free:
0.253 (Depositor), 0.260 (DCC)
R-Value Work:
0.198 (Depositor), 0.200 (DCC)
R-Value Observed:
0.200 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.

Sweis, R.F., Wang, Z., Algire, M., Arrowsmith, C.H., Brown, P.J., Chiang, G.G., Guo, J., Jakob, C.G., Kennedy, S., Li, F., Maag, D., Shaw, B., Soni, N.B., Vedadi, M., Pappano, W.N.

(2015) ACS Med Chem Lett 6: 695-700

PubMed: 26101576 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.5b00124
Primary Citation of Related Structures:
4YND

PubMed Abstract:
A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM). A cocrystal structure reveals the origin of enhanced potency, and effective suppression of p53K370 methylation is observed in a lung carcinoma (A549) cell line.

Organizational Affiliation

Discovery Research, AbbVie, Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.

Macromolecule Content

Total Structure Weight: 54.38 kDa
Atom Count: 3,633
Modelled Residue Count: 428
Deposited Residue Count: 461
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
N-lysine methyltransferase SMYD2	A	461	Homo sapiens	Mutation(s): 0 Gene Names: SMYD2, KMT3C EC: 2.1.1 (PDB Primary Data), 2.1.1.43 (PDB Primary Data), 2.1.1.354 (UniProt)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9NRG4 (Homo sapiens) Explore Q9NRG4 Go to UniProtKB: Q9NRG4
PHAROS: Q9NRG4 GTEx: ENSG00000143499
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q9NRG4
Sequence Annotations Expand
Reference Sequence LOADING

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
4GQ Query on 4GQ Download Ideal Coordinates CCD File SDF format, chain E [auth A] MOL2 format, chain E [auth A] mmCIF format, chain E [auth A]	E [auth A]	N-cyclohexyl-N~3~-[2-(3,4-dichlorophenyl)ethyl]-N-(2-{[(2R)-2-hydroxy-2-(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-8-yl)ethyl]amino}ethyl)-beta-alaninamide C₂₉ H₃₈ Cl₂ N₄ O₄ WVRBXBROEPXZHF-SANMLTNESA-N		Interactions Focus chain E [auth A] Interactions & Density Focus chain E [auth A]
SAM Query on SAM 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]	S-ADENOSYLMETHIONINE C₁₅ H₂₂ N₆ O₅ S MEFKEPWMEQBLKI-FCKMPRQPSA-N		Interactions Focus chain F [auth A] Interactions & Density Focus chain F [auth A]
ZN Query on ZN Download Ideal Coordinates CCD File SDF format, chain B [auth A] SDF format, chain C [auth A] SDF format, chain D [auth A] MOL2 format, chain B [auth A] MOL2 format, chain C [auth A] MOL2 format, chain D [auth A] mmCIF format, chain B [auth A] mmCIF format, chain C [auth A] mmCIF format, chain D [auth A]	B [auth A], C [auth A], D [auth A]	ZINC ION Zn PTFCDOFLOPIGGS-UHFFFAOYSA-N		Interactions Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A] Interactions & Density Focus chain B [auth A] Focus chain C [auth A] Focus chain D [auth A]

Binding Affinity Annotations
ID	Source	Binding Affinity
4GQ	BindingDB: 4YND	IC50: min: 2.8, max: 23 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.79 Å
R-Value Free: 0.253 (Depositor), 0.260 (DCC)
R-Value Work: 0.198 (Depositor), 0.200 (DCC)
R-Value Observed: 0.200 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 52.796	α = 90
b = 71.301	β = 90
c = 118.93	γ = 90

Software Package:

Software Name	Purpose
BUSTER	refinement
XDS	data reduction
XDS	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-05-20

Deposition Author(s):

Revision History (Full details and data files)

Version 1.0: 2015-05-20
Type: Initial release
Version 1.1: 2015-07-08
Changes: Database references
Version 1.2: 2023-09-27
Changes: Data collection, Database references, Derived calculations, Refinement description, Source and taxonomy, Structure summary