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- PDB-2iuh: Crystal structure of the PI3-kinase p85 N-terminal SH2 domain in ... -

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Basic information

Entry
Database: PDB / ID: 2iuh
TitleCrystal structure of the PI3-kinase p85 N-terminal SH2 domain in complex with c-Kit phosphotyrosyl peptide
Components
  • C-KIT PHOSPHOTYROSYL PEPTIDE
  • PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY ALPHA SUBUNIT
KeywordsTRANSFERASE / POLYMORPHISM / UBL CONJUGATION / PHOSPHORYLATION / P85 / SH2 / PI3K / SH2 DOMAIN / SH3 DOMAIN / PI3-KINASE / DISEASE MUTATION
Function / homology
Function and homology information


Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants ...Dasatinib-resistant KIT mutants / Imatinib-resistant KIT mutants / KIT mutants bind TKIs / Masitinib-resistant KIT mutants / Nilotinib-resistant KIT mutants / Regorafenib-resistant KIT mutants / Signaling by kinase domain mutants of KIT / Sunitinib-resistant KIT mutants / Signaling by juxtamembrane domain KIT mutants / Sorafenib-resistant KIT mutants / Signaling by extracellular domain mutants of KIT / stem cell factor receptor activity / hematopoietic stem cell migration / melanocyte adhesion / positive regulation of pyloric antrum smooth muscle contraction / positive regulation of colon smooth muscle contraction / erythropoietin-mediated signaling pathway / positive regulation of vascular associated smooth muscle cell differentiation / melanocyte migration / positive regulation of dendritic cell cytokine production / Kit signaling pathway / regulation of bile acid metabolic process / positive regulation of small intestine smooth muscle contraction / mast cell differentiation / positive regulation of mast cell proliferation / mast cell chemotaxis / Fc receptor signaling pathway / glycosphingolipid metabolic process / mast cell proliferation / positive regulation of long-term neuronal synaptic plasticity / perinuclear endoplasmic reticulum membrane / regulation of toll-like receptor 4 signaling pathway / detection of mechanical stimulus involved in sensory perception of sound / positive regulation of pseudopodium assembly / positive regulation of mast cell cytokine production / immature B cell differentiation / melanocyte differentiation / phosphatidylinositol kinase activity / phosphatidylinositol 3-kinase regulator activity / lymphoid progenitor cell differentiation / positive regulation of focal adhesion disassembly / IRS-mediated signalling / germ cell migration / phosphatidylinositol 3-kinase activator activity / interleukin-18-mediated signaling pathway / PI3K events in ERBB4 signaling / myeloid leukocyte migration / 1-phosphatidylinositol-3-kinase regulator activity / myeloid progenitor cell differentiation / phosphatidylinositol 3-kinase regulatory subunit binding / neurotrophin TRKA receptor binding / Activated NTRK2 signals through PI3K / Activated NTRK3 signals through PI3K / ErbB-3 class receptor binding / cis-Golgi network / RHOF GTPase cycle / kinase activator activity / transmembrane receptor protein tyrosine kinase adaptor activity / digestive tract development / RHOD GTPase cycle / Signaling by cytosolic FGFR1 fusion mutants / positive regulation of endoplasmic reticulum unfolded protein response / enzyme-substrate adaptor activity / negative regulation of programmed cell death / phosphatidylinositol 3-kinase complex, class IA / phosphatidylinositol 3-kinase complex / Nephrin family interactions / RND1 GTPase cycle / Costimulation by the CD28 family / positive regulation of leukocyte migration / MET activates PI3K/AKT signaling / RND2 GTPase cycle / embryonic hemopoiesis / PI3K/AKT activation / RND3 GTPase cycle / positive regulation of filopodium assembly / negative regulation of stress fiber assembly / lamellipodium assembly / growth hormone receptor signaling pathway / pigmentation / insulin binding / tongue development / megakaryocyte development / RHOV GTPase cycle / Regulation of KIT signaling / stem cell population maintenance / negative regulation of cell-matrix adhesion / RHOB GTPase cycle / mast cell degranulation / Signaling by ALK / GP1b-IX-V activation signalling / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / PI-3K cascade:FGFR3 / positive regulation of Notch signaling pathway / cytokine binding / PI-3K cascade:FGFR2 / RHOJ GTPase cycle / PI-3K cascade:FGFR4 / negative regulation of reproductive process / negative regulation of developmental process
Similarity search - Function
Mast/stem cell growth factor receptor / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Rho GTPase-activating protein domain ...Mast/stem cell growth factor receptor / Phosphatidylinositol 3-kinase regulatory subunit alpha, SH3 domain / PIK3R1, inter-SH2 domain / PI3K p85 subunit, C-terminal SH2 domain / PI3K regulatory subunit p85-related , inter-SH2 domain / PI3K p85 subunit, N-terminal SH2 domain / Phosphatidylinositol 3-kinase regulatory subunit P85 inter-SH2 domain / Tyrosine-protein kinase, receptor class III, conserved site / Receptor tyrosine kinase class III signature. / Rho GTPase-activating protein domain / RhoGAP domain / Rho GTPase-activating proteins domain profile. / GTPase-activator protein for Rho-like GTPases / Rho GTPase activation protein / SH2 domain / SHC Adaptor Protein / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Immunoglobulin subtype / Immunoglobulin / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / 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 / Alpha Beta
Similarity search - Domain/homology
Mast/stem cell growth factor receptor Kit / Phosphatidylinositol 3-kinase regulatory subunit alpha / Receptor protein-tyrosine kinase
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2 Å
AuthorsNolte, R.T. / Eck, M.J. / Schlessinger, J. / Shoelson, S.E. / Harrison, S.C.
CitationJournal: Nat.Struct.Biol. / Year: 1996
Title: Crystal Structure of the Pi 3-Kinase P85 Amino-Terminal Sh2 Domain and its Phosphopeptide Complexes
Authors: Nolte, R.T. / Eck, M.J. / Schlessinger, J. / Shoelson, S.E. / Harrison, S.C.
History
DepositionJun 3, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 6, 2006Provider: repository / Type: Initial release
Revision 1.1Oct 28, 2015Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Apr 28, 2021Group: Data collection / Derived calculations / Category: reflns / struct_conn
Item: _reflns.pdbx_redundancy / _struct_conn.pdbx_leaving_atom_flag
Remark 700 SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN ... SHEET THE SHEET STRUCTURE OF THIS MOLECULE IS BIFURCATED. IN ORDER TO REPRESENT THIS FEATURE IN THE SHEET RECORDS BELOW, TWO SHEETS ARE DEFINED.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY ALPHA SUBUNIT
B: C-KIT PHOSPHOTYROSYL PEPTIDE


Theoretical massNumber of molelcules
Total (without water)15,3052
Polymers15,3052
Non-polymers00
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1250 Å2
ΔGint-9.3 kcal/mol
Surface area7600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.950, 56.950, 68.170
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number92
Space group name H-MP41212

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Components

#1: Protein PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY ALPHA SUBUNIT / PI3-KINASE P85-ALPHA SUBUNIT / PTDINS-3-KINASE P85-ALPHA / PI3K


Mass: 13939.569 Da / Num. of mol.: 1 / Fragment: N-TERMINAL SH2 DOMAIN, RESIDUES 321-440
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PET / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P27986
#2: Protein/peptide C-KIT PHOSPHOTYROSYL PEPTIDE


Mass: 1365.445 Da / Num. of mol.: 1 / Fragment: RESIDUES 145-155
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: Q8TCG9, UniProt: P10721*PLUS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / Source method: isolated from a natural source / Formula: H2O
Compound detailsBINDS TO ACTIVATED (PHOSPHORYLATED) PROTEIN-TYR KINASES, THROUGH ITS SH2 DOMAIN, AND ACTS AS AN ...BINDS TO ACTIVATED (PHOSPHORYLATED) PROTEIN-TYR KINASES, THROUGH ITS SH2 DOMAIN, AND ACTS AS AN ADAPTER, MEDIATING THE ASSOCIATION OF THE P110 CATALYTIC UNIT TO THE PLASMA MEMBRANE. NECESSARY FOR THE INSULIN-STIMULATED INCREASE IN GLUCOSE UPTAKE AND GLYCOGEN SYNTHESIS IN INSULIN-SENSITIVE TISSUES.

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 1.9 Å3/Da / Density % sol: 34 %
Crystal growDetails: 0.1M NA CITRATE PH5.6, 0.2M NA/K TARTRATE, 2M AMMONIUM SULFATE

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Data collection

DiffractionMean temperature: 278 K
Diffraction sourceSource: ROTATING ANODE / Wavelength: 1.5418
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→20 Å / Num. obs: 8651 / % possible obs: 96.5 % / Observed criterion σ(I): 0 / Rmerge(I) obs: 0.05 / Net I/σ(I): 30.87
Reflection shellResolution: 2→2.1 Å / Rmerge(I) obs: 0.14 / Mean I/σ(I) obs: 10.84 / % possible all: 92.7

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Processing

SoftwareName: X-PLOR / Classification: refinement
RefinementMethod to determine structure: OTHER / Resolution: 2→15 Å / Cross valid method: THROUGHOUT / σ(F): 0
Details: THIS COODINATES FILE WAS DEPOSITED 10 YEARS AFTER THE PUBLICATION OF THE WORK. SOME OF THE DATA ARE MISSING AND ARE SHOWN AS '00000'
RfactorNum. reflection% reflection
Rfree0.245 --
Rwork0.1539 --
obs0.1539 0 0 %
Displacement parametersBiso mean: 17.65 Å2
Refinement stepCycle: LAST / Resolution: 2→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1018 0 0 101 1119
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.01
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg1.728
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it

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