6NT2

type 1 PRMT in complex with the inhibitor GSK3368715

PDB DOI: https://doi.org/10.2210/pdb6NT2/pdb

Classification: ANTITUMOR PROTEIN
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2019-01-28 Released: 2019-07-10
Deposition Author(s): Concha, N.O.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.48 Å
R-Value Free: 0.222
R-Value Work: 0.190
R-Value Observed: 0.192

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

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

Literature

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss.

Fedoriw, A., Rajapurkar, S.R., O'Brien, S., Gerhart, S.V., Mitchell, L.H., Adams, N.D., Rioux, N., Lingaraj, T., Ribich, S.A., Pappalardi, M.B., Shah, N., Laraio, J., Liu, Y., Butticello, M., Carpenter, C.L., Creasy, C., Korenchuk, S., McCabe, M.T., McHugh, C.F., Nagarajan, R., Wagner, C., Zappacosta, F., Annan, R., Concha, N.O., Thomas, R.A., Hart, T.K., Smith, J.J., Copeland, R.A., Moyer, M.P., Campbell, J., Stickland, K., Mills, J., Jacques-O'Hagan, S., Allain, C., Johnston, D., Raimondi, A., Porter Scott, M., Waters, N., Swinger, K., Boriack-Sjodin, A., Riera, T., Shapiro, G., Chesworth, R., Prinjha, R.K., Kruger, R.G., Barbash, O., Mohammad, H.P.

(2019) Cancer Cell 36: 100

PubMed: 31257072 Search on PubMed
DOI: https://doi.org/10.1016/j.ccell.2019.05.014
Primary Citation of Related Structures:
6NT2

PubMed Abstract:
Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection.

Organizational Affiliation

Epigenetics Research Unit, GlaxoSmithKline, Collegeville, PA 19426, USA.

Macromolecule Content

Total Structure Weight: 175.32 kDa
Atom Count: 12,135
Modelled Residue Count: 1,320
Deposited Residue Count: 1,484
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Protein arginine N-methyltransferase 1	A, B [auth D], C [auth B], D [auth C]	371	Homo sapiens	Mutation(s): 0 Gene Names: PRMT1, HMT2, HRMT1L2, IR1B4 EC: 2.1.1.319
UniProt & NIH Common Fund Data Resources
Find proteins for Q99873 (Homo sapiens) Explore Q99873 Go to UniProtKB: Q99873
PHAROS: Q99873 GTEx: ENSG00000126457
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q99873
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
SAH Query on SAH Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain EA [auth C] SDF format, chain N [auth D] SDF format, chain V [auth B] MOL2 format, chain E [auth A] MOL2 format, chain EA [auth C] MOL2 format, chain N [auth D] MOL2 format, chain V [auth B]	E [auth A], EA [auth C], N [auth D], V [auth B]	S-ADENOSYL-L-HOMOCYSTEINE C₁₄ H₂₀ N₆ O₅ S ZJUKTBDSGOFHSH-WFMPWKQPSA-N		Interactions Focus chain E [auth A] Focus chain EA [auth C] Focus chain N [auth D] Focus chain V [auth B] Interactions & Density Focus chain E [auth A] Focus chain EA [auth C] Focus chain N [auth D] Focus chain V [auth B]
KZS (Subject of Investigation/LOI) Query on KZS Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain FA [auth C] SDF format, chain O [auth D] SDF format, chain W [auth B] MOL2 format, chain F [auth A] MOL2 format, chain FA [auth C] MOL2 format, chain O [auth D] MOL2 format, chain W [auth B]	F [auth A], FA [auth C], O [auth D], W [auth B]	N~1~-({5-[4,4-bis(ethoxymethyl)cyclohexyl]-1H-pyrazol-4-yl}methyl)-N~1~,N~2~-dimethylethane-1,2-diamine C₂₀ H₃₈ N₄ O₂ SPEGERVLTUWZPA-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain FA [auth C] Focus chain O [auth D] Focus chain W [auth B] Interactions & Density Focus chain F [auth A] Focus chain FA [auth C] Focus chain O [auth D] Focus chain W [auth B]
DTT Query on DTT Download Ideal Coordinates CCD File SDF format, chain DA [auth B] MOL2 format, chain DA [auth B]	DA [auth B]	2,3-DIHYDROXY-1,4-DITHIOBUTANE C₄ H₁₀ O₂ S₂ VHJLVAABSRFDPM-IMJSIDKUSA-N		Interactions Focus chain DA [auth B] Interactions & Density Focus chain DA [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain AA [auth B] SDF format, chain BA [auth B] SDF format, chain CA [auth B] SDF format, chain G [auth A] SDF format, chain GA [auth C] SDF format, chain H [auth A] SDF format, chain HA [auth C] SDF format, chain I [auth A] SDF format, chain IA [auth C] SDF format, chain J [auth A] SDF format, chain JA [auth C] SDF format, chain K [auth A] SDF format, chain L [auth A] SDF format, chain M [auth A] SDF format, chain P [auth D] SDF format, chain Q [auth D] SDF format, chain R [auth D] SDF format, chain S [auth D] SDF format, chain T [auth D] SDF format, chain U [auth D] SDF format, chain X [auth B] SDF format, chain Y [auth B] SDF format, chain Z [auth B] MOL2 format, chain AA [auth B] MOL2 format, chain BA [auth B] MOL2 format, chain CA [auth B] MOL2 format, chain G [auth A] MOL2 format, chain GA [auth C] MOL2 format, chain H [auth A] MOL2 format, chain HA [auth C] MOL2 format, chain I [auth A] MOL2 format, chain IA [auth C] MOL2 format, chain J [auth A] MOL2 format, chain JA [auth C] MOL2 format, chain K [auth A] MOL2 format, chain L [auth A] MOL2 format, chain M [auth A] MOL2 format, chain P [auth D] MOL2 format, chain Q [auth D] MOL2 format, chain R [auth D] MOL2 format, chain S [auth D] MOL2 format, chain T [auth D] MOL2 format, chain U [auth D] MOL2 format, chain X [auth B] MOL2 format, chain Y [auth B] MOL2 format, chain Z [auth B]	AA [auth B] BA [auth B] CA [auth B] G [auth A] GA [auth C] AA [auth B], BA [auth B], CA [auth B], G [auth A], GA [auth C], H [auth A], HA [auth C], I [auth A], IA [auth C], J [auth A], JA [auth C], K [auth A], L [auth A], M [auth A], P [auth D], Q [auth D], R [auth D], S [auth D], T [auth D], U [auth D], X [auth B], Y [auth B], Z [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain HA [auth C] Focus chain I [auth A] Focus chain IA [auth C] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain P [auth D] Focus chain Q [auth D] Focus chain R [auth D] Focus chain S [auth D] Focus chain T [auth D] Focus chain U [auth D] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B] Interactions & Density Focus chain AA [auth B] Focus chain BA [auth B] Focus chain CA [auth B] Focus chain G [auth A] Focus chain GA [auth C] Focus chain H [auth A] Focus chain HA [auth C] Focus chain I [auth A] Focus chain IA [auth C] Focus chain J [auth A] Focus chain JA [auth C] Focus chain K [auth A] Focus chain L [auth A] Focus chain M [auth A] Focus chain P [auth D] Focus chain Q [auth D] Focus chain R [auth D] Focus chain S [auth D] Focus chain T [auth D] Focus chain U [auth D] Focus chain X [auth B] Focus chain Y [auth B] Focus chain Z [auth B]