[English] 日本語
Yorodumi
- PDB-8u0h: Crystal structure of PTPN2 with a PROTAC -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8u0h
TitleCrystal structure of PTPN2 with a PROTAC
ComponentsPTPN2
KeywordsHYDROLASE / protein tyrosine phosphatase / degrader / PROTAC
Function / homology
Function and homology information


negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / negative regulation of macrophage differentiation / regulation of type II interferon-mediated signaling pathway / negative regulation of chemotaxis ...negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / negative regulation of macrophage differentiation / regulation of type II interferon-mediated signaling pathway / negative regulation of chemotaxis / negative regulation of tyrosine phosphorylation of STAT protein / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of receptor signaling pathway via JAK-STAT / Interleukin-37 signaling / syntaxin binding / negative regulation of type I interferon-mediated signaling pathway / negative regulation of T cell receptor signaling pathway / STAT family protein binding / regulation of hepatocyte growth factor receptor signaling pathway / insulin receptor recycling / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of type II interferon-mediated signaling pathway / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of lipid storage / T cell differentiation / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of IFNG signaling / positive regulation of gluconeogenesis / negative regulation of insulin receptor signaling pathway / B cell differentiation / protein-tyrosine-phosphatase / erythrocyte differentiation / protein tyrosine phosphatase activity / endosome lumen / PKR-mediated signaling / Negative regulation of MET activity / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / negative regulation of inflammatory response / integrin binding / insulin receptor signaling pathway / glucose homeostasis / negative regulation of cell population proliferation / protein kinase binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-1/2 / : / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site ...Protein-tyrosine phosphatase, non-receptor type-1/2 / : / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine-specific protein phosphatases domain / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like
Similarity search - Domain/homology
ACETATE ION / : / Tyrosine-protein phosphatase non-receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.93 Å
AuthorsJain, R. / Longenecker, K. / Qiu, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Commun Chem / Year: 2024
Title: Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex.
Authors: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark ...Authors: Qi Hao / Manoj K Rathinaswamy / Kelly L Klinge / Matthew Bratkowski / Amirhossein Mafi / Christina K Baumgartner / Keith M Hamel / Gesine K Veits / Rinku Jain / Claudio Catalano / Mark Fitzgerald / Alexander W Hird / Eunice Park / Harit U Vora / James A Henderson / Kenton Longenecker / Charles W Hutchins / Wei Qiu / Giovanna Scapin / Qi Sun / Vincent S Stoll / Chaohong Sun / Ping Li / Dan Eaton / David Stokoe / Stewart L Fisher / Christopher G Nasveschuk / Marcia Paddock / Michael E Kort /
Abstract: PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in ...PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.
History
DepositionAug 29, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: PTPN2
B: PTPN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)78,0287
Polymers75,9322
Non-polymers2,0965
Water6,936385
1
A: PTPN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0264
Polymers37,9661
Non-polymers1,0603
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: PTPN2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)39,0033
Polymers37,9661
Non-polymers1,0372
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)77.180, 126.510, 150.210
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-803-

NA

21A-1065-

HOH

31B-1007-

HOH

-
Components

#1: Protein PTPN2 / Mer tyrosine kinase domain / Tyrosine-protein phosphatase non-receptor type 2 / T-cell protein- ...Mer tyrosine kinase domain / Tyrosine-protein phosphatase non-receptor type 2 / T-cell protein-tyrosine phosphatase / TCPTP


Mass: 37966.000 Da / Num. of mol.: 2 / Fragment: UNP residues 1-314
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN2, PTPT / Cell line (production host): sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P17706, protein-tyrosine-phosphatase
#2: Chemical ChemComp-UB0 / (5P)-3-(carboxymethoxy)-4-chloro-5-(3-{[(4S)-1-({3-[2-(4-{3-[(3R)-2,6-dioxopiperidin-3-yl]-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl}piperidin-1-yl)acetamido]phenyl}methanesulfonyl)-2,2-dimethylpiperidin-4-yl]amino}phenyl)thiophene-2-carboxylic acid


Mass: 977.497 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C46H49ClN6O12S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 385 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.41 Å3/Da / Density % sol: 49.06 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 6.9
Details: 0.49M Sodium phosphate monobasic monohydrate, 0.91M Potassium phosphate dibasic

-
Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.93→38.59 Å / Num. obs: 365575 / % possible obs: 99.985 % / Redundancy: 6.6 % / Biso Wilson estimate: 32.32 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.06263 / Net I/σ(I): 17.22
Reflection shellResolution: 1.93→1.999 Å / Rmerge(I) obs: 0.6897 / Num. unique obs: 5493 / CC1/2: 0.829

-
Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.93→38.59 Å / SU ML: 0.2177 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 19.3519
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1917 2780 5.01 %
Rwork0.1726 52705 -
obs0.1735 55485 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 38.32 Å2
Refinement stepCycle: LAST / Resolution: 1.93→38.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4558 0 143 385 5086
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01824881
X-RAY DIFFRACTIONf_angle_d1.7196643
X-RAY DIFFRACTIONf_chiral_restr0.1158702
X-RAY DIFFRACTIONf_plane_restr0.011936
X-RAY DIFFRACTIONf_dihedral_angle_d14.77311902
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.93-1.960.32711270.2782601X-RAY DIFFRACTION99.89
1.96-20.28541160.24492653X-RAY DIFFRACTION99.96
2-2.040.24371460.22642606X-RAY DIFFRACTION99.96
2.04-2.080.25021460.2142576X-RAY DIFFRACTION99.89
2.08-2.120.25971580.20182593X-RAY DIFFRACTION99.93
2.12-2.170.20531480.19312616X-RAY DIFFRACTION100
2.17-2.230.20571450.19322586X-RAY DIFFRACTION99.96
2.23-2.290.21941510.19312596X-RAY DIFFRACTION99.93
2.29-2.350.20161300.18642642X-RAY DIFFRACTION99.82
2.36-2.430.22081380.19642617X-RAY DIFFRACTION99.96
2.43-2.520.24141530.19362584X-RAY DIFFRACTION99.82
2.52-2.620.22181390.18132620X-RAY DIFFRACTION99.86
2.62-2.740.22421260.18872683X-RAY DIFFRACTION99.96
2.74-2.880.1851690.18342591X-RAY DIFFRACTION99.96
2.88-3.060.2141220.18582656X-RAY DIFFRACTION99.93
3.06-3.30.18421170.1732645X-RAY DIFFRACTION99.68
3.3-3.630.18131290.15332663X-RAY DIFFRACTION99.71
3.63-4.160.15521580.14452668X-RAY DIFFRACTION99.89
4.16-5.230.12521320.13762698X-RAY DIFFRACTION99.68
5.23-38.590.20421300.16852811X-RAY DIFFRACTION99.49

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbjlvh1.pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more