5USY

JAK2 JH1 in complex with JNJ-7706621

PDB DOI: https://doi.org/10.2210/pdb5USY/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Spodoptera frugiperda
Mutation(s): No

Deposited: 2017-02-14 Released: 2017-06-07
Deposition Author(s): Puleo, D.E., Schlessinger, J.
Funding Organization(s): National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), Gilead Sciences

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.216
R-Value Work: 0.176
R-Value Observed: 0.178

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.7 of the entry. See complete history.

Literature

Identification and Characterization of JAK2 Pseudokinase Domain Small Molecule Binders.

Puleo, D.E., Kucera, K., Hammaren, H.M., Ungureanu, D., Newton, A.S., Silvennoinen, O., Jorgensen, W.L., Schlessinger, J.

(2017) ACS Med Chem Lett 8: 618-621

PubMed: 28626521 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/acsmedchemlett.7b00153
Primary Citation of Related Structures:
5USY, 5USZ, 5UT0, 5UT1, 5UT2, 5UT3

PubMed Abstract:
Janus kinases (JAKs) regulate hematopoiesis via the cytokine-mediated JAK-STAT signaling pathway. JAKs contain tandem C-terminal pseudokinase (JH2) and tyrosine kinase (JH1) domains. The JAK2 pseudokinase domain adopts a protein kinase fold and, despite its pseudokinase designation, binds ATP with micromolar affinity. Recent evidence shows that displacing ATP from the JAK2 JH2 domain alters the hyperactivation state of the oncogenic JAK2 V617F protein while sparing the wild type JAK2 protein. In this study, small molecule binders of JAK2 JH2 were identified via an in vitro screen. Top hits were characterized using biophysical and structural approaches. Development of pseudokinase-selective compounds may offer novel pharmacological opportunities for treating cancers driven by JAK2 V617F and other oncogenic JAK mutants.

Organizational Affiliation

Department of Pharmacology and Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States.

Macromolecule Content

Total Structure Weight: 76.34 kDa
Atom Count: 5,438
Modelled Residue Count: 576
Deposited Residue Count: 632
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Tyrosine-protein kinase JAK2	A, B	316	Homo sapiens	Mutation(s): 0 Gene Names: JAK2 EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for O60674 (Homo sapiens) Explore O60674 Go to UniProtKB: O60674
PHAROS: O60674 GTEx: ENSG00000096968
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O60674
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
SKE Query on SKE Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain H [auth B] MOL2 format, chain C [auth A] MOL2 format, chain H [auth B] mmCIF format, chain C [auth A] mmCIF format, chain H [auth B]	C [auth A], H [auth B]	4-({5-amino-1-[(2,6-difluorophenyl)carbonyl]-1H-1,2,4-triazol-3-yl}amino)benzenesulfonamide C₁₅ H₁₂ F₂ N₆ O₃ S KDKUVYLMPJIGKA-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Focus chain H [auth B] Interactions & Density Focus chain C [auth A] Focus chain H [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain I [auth B] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain I [auth B] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain I [auth B] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B]	D [auth A], E [auth A], I [auth B], J [auth B], K [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain I [auth B] Focus chain J [auth B] Focus chain K [auth B]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain G [auth A] SDF format, chain L [auth B] MOL2 format, chain F [auth A] MOL2 format, chain G [auth A] MOL2 format, chain L [auth B] mmCIF format, chain F [auth A] mmCIF format, chain G [auth A] mmCIF format, chain L [auth B]	F [auth A], G [auth A], L [auth B]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain F [auth A] Focus chain G [auth A] Focus chain L [auth B] Interactions & Density Focus chain F [auth A] Focus chain G [auth A] Focus chain L [auth B]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
PTR Query on PTR	A, B	L-PEPTIDE LINKING	C₉ H₁₂ N O₆ P		TYR

Binding Affinity Annotations
ID	Source	Binding Affinity
SKE	BindingDB: 5USY	Ki: 2.20e+5 (nM) from 1 assay(s)
		Kd: min: 31, max: 800 (nM) from 9 assay(s)
		IC50: min: 1, max: 2960 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.00 Å
R-Value Free: 0.216
R-Value Work: 0.176
R-Value Observed: 0.178
Space Group: C 1 2 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 137.017	α = 90
b = 68.965	β = 127.16
c = 100.567	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
HKL-2000	data reduction
SCALEPACK	data scaling
PHASER	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2017-06-07

Deposition Author(s):

Puleo, D.E.

Schlessinger, J.

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	GM007324
Gilead Sciences	United States	YG-003-13

Revision History (Full details and data files)

Version 1.0: 2017-06-07
Type: Initial release
Version 1.1: 2017-07-05
Changes: Database references
Version 1.2: 2017-09-13
Changes: Author supporting evidence
Version 1.3: 2017-09-27
Changes: Data collection
Version 1.4: 2020-01-01
Changes: Author supporting evidence
Version 1.5: 2023-10-04
Changes: Data collection, Database references, Refinement description
Version 1.6: 2023-11-15
Changes: Data collection
Version 1.7: 2024-11-06
Changes: Structure summary