4WNP

Structure of ULK1 bound to a potent inhibitor

PDB DOI: https://doi.org/10.2210/pdb4WNP/pdb

Classification: TRANSFERASE/TRANSFERASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2014-10-14 Released: 2015-01-14
Deposition Author(s): Lazarus, M.B., Novotny, C.J., Shokat, K.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.88 Å
R-Value Free: 0.226
R-Value Work: 0.192
R-Value Observed: 0.194

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Structure of the Human Autophagy Initiating Kinase ULK1 in Complex with Potent Inhibitors.

Lazarus, M.B., Novotny, C.J., Shokat, K.M.

(2015) ACS Chem Biol 10: 257-261

PubMed: 25551253 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1021/cb500835z
Primary Citation of Related Structures:
4WNO, 4WNP

PubMed Abstract:
Autophagy is a conserved cellular process that involves the degradation of cellular components for energy maintenance and cytoplasmic quality control that has recently gained interest as a novel target for a variety of human diseases, including cancer. A prime candidate to determine the potential therapeutic benefit of targeting autophagy is the kinase ULK1, whose activation initiates autophagy. Here, we report the first structures of ULK1, in complex with multiple potent inhibitors. These structures show features unique to the enzyme and will provide a path for the rational design of selective compounds as cellular probes and potential therapeutics.

Organizational Affiliation

Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco , San Francisco, California 94158, United States.

Macromolecule Content

Total Structure Weight: 131.05 kDa
Atom Count: 9,214
Modelled Residue Count: 1,092
Deposited Residue Count: 1,148
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Serine/threonine-protein kinase ULK1	A, B, C, D	287	Homo sapiens	Mutation(s): 2 Gene Names: ULK1, KIAA0722 EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for O75385 (Homo sapiens) Explore O75385 Go to UniProtKB: O75385
PHAROS: O75385 GTEx: ENSG00000177169
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	O75385
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
3RJ Query on 3RJ Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain H [auth B] SDF format, chain I [auth C] SDF format, chain J [auth D] MOL2 format, chain G [auth A] MOL2 format, chain H [auth B] MOL2 format, chain I [auth C] MOL2 format, chain J [auth D]	G [auth A], H [auth B], I [auth C], J [auth D]	N~2~-(1H-benzimidazol-6-yl)-N~4~-(5-cyclobutyl-1H-pyrazol-3-yl)quinazoline-2,4-diamine C₂₂ H₂₀ N₈ DLCOOKRUECVLCI-UHFFFAOYSA-N		Interactions Focus chain G [auth A] Focus chain H [auth B] Focus chain I [auth C] Focus chain J [auth D] Interactions & Density Focus chain G [auth A] Focus chain H [auth B] Focus chain I [auth C] Focus chain J [auth D]
GOL Query on GOL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A]	E [auth A], F [auth A]	GLYCEROL C₃ H₈ O₃ PEDCQBHIVMGVHV-UHFFFAOYSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Interactions & Density Focus chain E [auth A] Focus chain F [auth A]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
TPO Query on TPO	A, B, C, D	L-PEPTIDE LINKING	C₄ H₁₀ N O₆ P		THR

Binding Affinity Annotations
ID	Source	Binding Affinity
3RJ	Binding MOAD: 4WNP	IC50: 8 (nM) from 1 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.88 Å
R-Value Free: 0.226
R-Value Work: 0.192
R-Value Observed: 0.194
Space Group: P 2 2 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 100.41	α = 90
b = 113.8	β = 90
c = 100.63	γ = 90

Software Package:

Software Name	Purpose
PHENIX	refinement
iMOSFLM	data reduction
SCALA	data scaling
PHASER	phasing

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2015-01-14

Deposition Author(s):

Lazarus, M.B.

Novotny, C.J.

Shokat, K.M.

Revision History (Full details and data files)

Version 1.0: 2015-01-14
Type: Initial release
Version 1.1: 2015-01-28
Changes: Database references
Version 1.2: 2017-11-22
Changes: Derived calculations, Other, Refinement description, Source and taxonomy, Structure summary
Version 1.3: 2023-12-27
Changes: Data collection, Database references, Refinement description