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- PDB-6e2p: Structure of human JAK2 FERM/SH2 in complex with Leptin Receptor -

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Basic information

Entry
Database: PDB / ID: 6e2p
TitleStructure of human JAK2 FERM/SH2 in complex with Leptin Receptor
Components
  • Leptin receptor
  • Tyrosine-protein kinase JAK2
KeywordsSIGNALING PROTEIN / Cytokine Receptor / Leptin / Signal Transduction
Function / homology
Function and homology information


multicellular organism development / leptin receptor activity / sexual reproduction / regulation of bone remodeling / regulation of transport / leptin-mediated signaling pathway / bone growth / energy reserve metabolic process / regulation of feeding behavior / nuclear receptor-mediated mineralocorticoid signaling pathway ...multicellular organism development / leptin receptor activity / sexual reproduction / regulation of bone remodeling / regulation of transport / leptin-mediated signaling pathway / bone growth / energy reserve metabolic process / regulation of feeding behavior / nuclear receptor-mediated mineralocorticoid signaling pathway / response to leptin / response to interleukin-12 / histone H3Y41 kinase activity / mammary gland epithelium development / positive regulation of growth hormone receptor signaling pathway / interleukin-35-mediated signaling pathway / positive regulation of growth factor dependent skeletal muscle satellite cell proliferation / regulation of postsynapse to nucleus signaling pathway / granulocyte-macrophage colony-stimulating factor signaling pathway / thrombopoietin-mediated signaling pathway / Signaling by Erythropoietin / Erythropoietin activates STAT5 / collagen-activated signaling pathway / interleukin-12 receptor binding / activation of Janus kinase activity / Erythropoietin activates Phospholipase C gamma (PLCG) / regulation of alpha-beta T cell activation / type 1 angiotensin receptor binding / post-embryonic hemopoiesis / positive regulation of MHC class II biosynthetic process / erythropoietin-mediated signaling pathway / Interleukin-23 signaling / positive regulation of cell-substrate adhesion / interleukin-12-mediated signaling pathway / positive regulation of leukocyte proliferation / positive regulation of platelet activation / interleukin-23-mediated signaling pathway / intrinsic apoptotic signaling pathway in response to oxidative stress / interleukin-3-mediated signaling pathway / interleukin-5-mediated signaling pathway / Interleukin-12 signaling / positive regulation of epithelial cell apoptotic process / acetylcholine receptor binding / Signaling by Leptin / Interleukin-27 signaling / IL-6-type cytokine receptor ligand interactions / Interleukin-35 Signalling / regulation of nitric oxide biosynthetic process / platelet-derived growth factor receptor signaling pathway / positive regulation of platelet aggregation / growth hormone receptor binding / cell surface receptor signaling pathway via STAT / axon regeneration / cytokine receptor activity / response to hydroperoxide / negative regulation of cell-cell adhesion / growth hormone receptor signaling pathway / extrinsic component of plasma membrane / regulation of receptor signaling pathway via JAK-STAT / Interleukin-20 family signaling / Interleukin-6 signaling / IFNG signaling activates MAPKs / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / enzyme-linked receptor protein signaling pathway / interleukin-6-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / regulation of cytokine production involved in inflammatory response / peptide hormone receptor binding / positive regulation of tyrosine phosphorylation of STAT protein / MAPK3 (ERK1) activation / mesoderm development / MAPK1 (ERK2) activation / Prolactin receptor signaling / cytokine binding / energy homeostasis / positive regulation of SMAD protein signal transduction / signaling receptor activator activity / peptide hormone binding / T cell differentiation / negative regulation of cardiac muscle cell apoptotic process / phagocytosis / Interleukin-3, Interleukin-5 and GM-CSF signaling / growth hormone receptor signaling pathway via JAK-STAT / response to tumor necrosis factor / insulin receptor substrate binding / lipopolysaccharide-mediated signaling pathway / Interleukin receptor SHC signaling / Regulation of IFNG signaling / type II interferon-mediated signaling pathway / Growth hormone receptor signaling / extrinsic apoptotic signaling pathway / positive regulation of vascular associated smooth muscle cell proliferation / cell surface receptor signaling pathway via JAK-STAT / phosphatidylinositol 3-kinase binding / transport across blood-brain barrier / Erythropoietin activates RAS / Signaling by CSF3 (G-CSF) / actin filament polymerization / positive regulation of T cell proliferation / negative regulation of cytokine production involved in inflammatory response
Similarity search - Function
Leptin receptor, immunoglobulin-like domain / Obesity receptor immunoglobulin like domain / Short hematopoietin receptor, family 1, conserved site / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain ...Leptin receptor, immunoglobulin-like domain / Obesity receptor immunoglobulin like domain / Short hematopoietin receptor, family 1, conserved site / Immunoglobulin C2-set-like, ligand-binding / Ig-like C2-type domain / Long hematopoietin receptor, Gp130 family 2, conserved site / Long hematopoietin receptor, gp130 family signature. / Tyrosine-protein kinase, non-receptor Jak2 / Janus kinase 2, pseudokinase domain / Janus kinase 2, catalytic domain / Tyrosine-protein kinase JAK2, SH2 domain / JAK2, FERM domain C-lobe / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / : / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / SH2 domain / SH2 domain / SHC Adaptor Protein / Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB) / PH-domain like / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Fibronectin type III domain / Fibronectin type 3 domain / SH2 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Roll / Ig-like domain profile. / Immunoglobulin-like domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Mainly Beta / Alpha Beta
Similarity search - Domain/homology
Tyrosine-protein kinase JAK2 / Leptin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.83 Å
AuthorsFerrao, R. / Lupardus, P.J. / Wallweber, H.J.A.
CitationJournal: Elife / Year: 2018
Title: Receptor-mediated dimerization of JAK2 FERM domains is required for JAK2 activation.
Authors: Ferrao, R.D. / Wallweber, H. / Lupardus, P.J.
History
DepositionJul 11, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase JAK2
B: Tyrosine-protein kinase JAK2
C: Leptin receptor
D: Leptin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,1045
Polymers129,0084
Non-polymers961
Water48627
1
A: Tyrosine-protein kinase JAK2
C: Leptin receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6003
Polymers64,5042
Non-polymers961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1900 Å2
ΔGint-27 kcal/mol
Surface area23540 Å2
MethodPISA
2
B: Tyrosine-protein kinase JAK2
D: Leptin receptor


Theoretical massNumber of molelcules
Total (without water)64,5042
Polymers64,5042
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1600 Å2
ΔGint-14 kcal/mol
Surface area22560 Å2
MethodPISA
Unit cell
Length a, b, c (Å)263.870, 263.870, 101.080
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11B-476-

ASP

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Components

#1: Protein Tyrosine-protein kinase JAK2 / Janus kinase 2 / JAK-2


Mass: 55919.613 Da / Num. of mol.: 2 / Fragment: FERM/SH2 (UNP residues 36-514)
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JAK2 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O60674, non-specific protein-tyrosine kinase
#2: Protein Leptin receptor / LEPR / LEP-R / HuB219 / OB receptor / OB-R


Mass: 8584.573 Da / Num. of mol.: 2 / Fragment: UNP residues 863-933
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LEPR, DB, OBR / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P48357
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 27 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

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

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Sample preparation

CrystalDensity Matthews: 3.94 Å3/Da / Density % sol: 68.76 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 0.1 M MES, pH 6.5, 0.2 M magnesium chloride, 5-10% PEG4000, 10% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 10, 2015
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.83→43.19 Å / Num. obs: 49544 / % possible obs: 99.58 % / Redundancy: 13.4 % / Biso Wilson estimate: 78.56 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.1052 / Rpim(I) all: 0.02946 / Rrim(I) all: 0.1093 / Net I/σ(I): 21.83
Reflection shellResolution: 2.83→2.931 Å / Redundancy: 13.7 % / Rmerge(I) obs: 1.597 / Mean I/σ(I) obs: 2.03 / Num. unique obs: 4861 / CC1/2: 0.798 / Rpim(I) all: 0.4413 / Rrim(I) all: 1.658 / % possible all: 99.47

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Processing

Software
NameVersionClassification
PHENIX(1.10.1-2155_2155: ???)refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 4Z32

4z32


Resolution: 2.83→43.186 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 26.77
RfactorNum. reflection% reflection
Rfree0.2426 1999 4.04 %
Rwork0.2274 --
obs0.228 49499 99.63 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 106.19 Å2
Refinement stepCycle: LAST / Resolution: 2.83→43.186 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7569 0 5 27 7601
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0037762
X-RAY DIFFRACTIONf_angle_d0.60310514
X-RAY DIFFRACTIONf_dihedral_angle_d15.644608
X-RAY DIFFRACTIONf_chiral_restr0.0421147
X-RAY DIFFRACTIONf_plane_restr0.0041333
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.8303-2.90110.39171390.34143313X-RAY DIFFRACTION99
2.9011-2.97950.33941420.3063359X-RAY DIFFRACTION100
2.9795-3.06710.29521410.28753352X-RAY DIFFRACTION100
3.0671-3.16610.31821410.28523350X-RAY DIFFRACTION100
3.1661-3.27920.31841410.2693344X-RAY DIFFRACTION100
3.2792-3.41050.29091410.27773364X-RAY DIFFRACTION100
3.4105-3.56560.26481410.24533371X-RAY DIFFRACTION100
3.5656-3.75350.27341430.22873379X-RAY DIFFRACTION100
3.7535-3.98850.25121420.21143383X-RAY DIFFRACTION100
3.9885-4.29620.20561430.1973376X-RAY DIFFRACTION100
4.2962-4.72810.19051430.17633413X-RAY DIFFRACTION100
4.7281-5.41110.18131440.18483419X-RAY DIFFRACTION99
5.4111-6.81310.24411450.253468X-RAY DIFFRACTION99
6.8131-43.19090.23761530.22943609X-RAY DIFFRACTION98
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.3318-1.2036-1.24612.48282.57446.0985-0.3089-0.54880.10920.19790.5805-0.1348-0.4320.88-0.23960.86070.03730.22530.7512-0.13230.5176-48.9289-51.171819.2214
22.8087-2.25111.15834.3936-1.33772.6670.1944-0.1007-1.1991-0.36160.0151.0910.2209-0.1846-0.18090.6068-0.08940.08690.52320.0451.5197-80.205-81.3276-6.6159
33.05560.35131.293.00631.56454.1244-0.3261-0.7321-0.05130.512-0.38530.37570.6988-0.59090.62261.51580.57440.23941.090.04610.8381-56.9387-49.97857.5579
44.7732-0.25650.97873.34620.50373.1473-0.18750.18690.3004-0.9634-0.21940.71080.24040.25360.37251.45920.111-0.07930.8811-0.16391.0375-89.277-53.1912-28.5747
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1(chain 'A' and resid 38 through 515)
2X-RAY DIFFRACTION2(chain 'B' and resid 41 through 514)
3X-RAY DIFFRACTION3(chain 'C' and resid 866 through 885)
4X-RAY DIFFRACTION4(chain 'D' and resid 868 through 885)

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