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- PDB-5hpr: Insulin with proline analog HyP at position B28 in the T2 state -

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Basic information

Entry
Database: PDB / ID: 5hpr
TitleInsulin with proline analog HyP at position B28 in the T2 state
Components
  • Insulin A-Chain
  • Insulin B-Chain
KeywordsHORMONE / Insulin / non-canonical amino acid / hydroxyproline / non-natural amino acid / unnatural amino acid
Function / homology
Function and homology information


Signaling by Insulin receptor / negative regulation of glycogen catabolic process / alpha-beta T cell activation / Insulin processing / IRS activation / Insulin receptor recycling / negative regulation of NAD(P)H oxidase activity / nitric oxide-cGMP-mediated signaling pathway / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process ...Signaling by Insulin receptor / negative regulation of glycogen catabolic process / alpha-beta T cell activation / Insulin processing / IRS activation / Insulin receptor recycling / negative regulation of NAD(P)H oxidase activity / nitric oxide-cGMP-mediated signaling pathway / negative regulation of feeding behavior / negative regulation of fatty acid metabolic process / regulation of protein secretion / Regulation of gene expression in beta cells / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of respiratory burst involved in inflammatory response / negative regulation of gluconeogenesis / negative regulation of reactive oxygen species biosynthetic process / positive regulation of cellular protein metabolic process / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / Regulation of insulin secretion / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / regulation of cellular amino acid metabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of nitric oxide mediated signal transduction / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Signal attenuation / negative regulation of lipid catabolic process / negative regulation of protein secretion / positive regulation of lipid biosynthetic process / fatty acid homeostasis / endosome lumen / transport vesicle / positive regulation of insulin receptor signaling pathway / endoplasmic reticulum-Golgi intermediate compartment membrane / neuron projection maintenance / insulin-like growth factor receptor binding / positive regulation of protein autophosphorylation / positive regulation of glycolytic process / negative regulation of acute inflammatory response / regulation of transmembrane transporter activity / positive regulation of cell differentiation / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / regulation of synaptic plasticity / positive regulation of brown fat cell differentiation / cognition / regulation of protein localization / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / acute-phase response / activation of protein kinase B activity / positive regulation of glucose import / vasodilation / hormone activity / negative regulation of proteolysis / negative regulation of protein catabolic process / insulin receptor binding / positive regulation of protein localization to nucleus / insulin receptor signaling pathway / glucose metabolic process / Golgi lumen / positive regulation of nitric-oxide synthase activity / cell-cell signaling / glucose homeostasis / wound healing / endoplasmic reticulum to Golgi vesicle-mediated transport / positive regulation of MAPK cascade / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of phosphatidylinositol 3-kinase signaling / positive regulation of cell growth / secretory granule lumen / protease binding / positive regulation of NF-kappaB transcription factor activity / positive regulation of cell migration / positive regulation of protein kinase B signaling / Amyloid fiber formation / Golgi membrane / G protein-coupled receptor signaling pathway / amyloid fibril formation / endoplasmic reticulum lumen / regulation of transcription, DNA-templated / positive regulation of gene expression / positive regulation of cell population proliferation / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin-like superfamily / Insulin family signature.
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.33 Å
AuthorsLieblich, S.A. / Fang, K.Y. / Cahn, J.K.B. / Tirrell, D.A.
Funding support Denmark, 1items
OrganizationGrant numberCountry
Novo Nordisk Foundation Denmark
CitationJournal: J. Am. Chem. Soc. / Year: 2017
Title: 4S-Hydroxylation of Insulin at ProB28 Accelerates Hexamer Dissociation and Delays Fibrillation.
Authors: Lieblich, S.A. / Fang, K.Y. / Cahn, J.K.B. / Rawson, J. / LeBon, J. / Ku, H.T. / Tirrell, D.A.
History
DepositionJan 21, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2017Provider: repository / Type: Initial release
Revision 1.1Jul 12, 2017Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 15, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)5,9494
Polymers5,8342
Non-polymers1152
Water99155
1
A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules

A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8978
Polymers11,6674
Non-polymers2304
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation16_554x,-y,-z-1/21
Buried area4960 Å2
ΔGint-45 kcal/mol
Surface area5360 Å2
MethodPISA
2
A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules

A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules

A: Insulin A-Chain
B: Insulin B-Chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,84612
Polymers17,5016
Non-polymers3456
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_555z,x,y1
crystal symmetry operation9_555y,z,x1
Buried area7010 Å2
ΔGint-52 kcal/mol
Surface area8270 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)78.245, 78.245, 78.245
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number199
Space group name H-MI213
Components on special symmetry positions
IDModelComponents
11B-101-

NA

21B-223-

HOH

31B-231-

HOH

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Components

#1: Protein/peptide Insulin A-Chain


Mass: 2383.698 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Plasmid: pQE80L / Production host: Escherichia coli (E. coli) / Strain (production host): CAG18515 / References: UniProt: P01308
#2: Protein/peptide Insulin B-Chain


Mass: 3449.953 Da / Num. of mol.: 1 / Mutation: Pro28Hyp
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Plasmid: pQE80L / Production host: Escherichia coli (E. coli) / Strain (production host): CAG18515 / References: UniProt: P01308
#3: Chemical ChemComp-NA / SODIUM ION / Sodium


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 55 / 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: 3.42 Å3/Da / Density % sol: 64.05 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 300 mM Tris, 0.5 mM zinc acetate, 8.5% acetone, 0.5 M sodium citrate

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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 24, 2015
RadiationMonochromator: LIQUID NITROGEN-COOLED DOUBLE CRYSTAL K-B FOCUSING MIRRORS
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.33→55.33 Å / Num. obs: 18244 / % possible obs: 99.4 % / Redundancy: 5.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.054 / Net I/σ(I): 17.4
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.33-1.363.30.2764188.8
7.18-39.125.90.0431.2199

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0069refinement
Aimless0.3.11data scaling
PDB_EXTRACT3.15data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3T2A
Resolution: 1.33→55.33 Å / Cor.coef. Fo:Fc: 0.978 / Cor.coef. Fo:Fc free: 0.96 / SU B: 1.041 / SU ML: 0.02 / Cross valid method: THROUGHOUT / ESU R: 0.033 / ESU R Free: 0.037 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.16383 939 5.1 %RANDOM
Rwork0.12457 ---
obs0.12651 17298 99.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.801 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: LAST / Resolution: 1.33→55.33 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms398 0 7 55 460
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0340.019439
X-RAY DIFFRACTIONr_bond_other_d0.0030.02400
X-RAY DIFFRACTIONr_angle_refined_deg1.3861.963595
X-RAY DIFFRACTIONr_angle_other_deg0.943918
X-RAY DIFFRACTIONr_dihedral_angle_1_deg
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.120.269
X-RAY DIFFRACTIONr_gen_planes_refined0.0180.02493
X-RAY DIFFRACTIONr_gen_planes_other0.0110.02113
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.1851.656210
X-RAY DIFFRACTIONr_mcbond_other3.1751.636209
X-RAY DIFFRACTIONr_mcangle_it3.3122.366255
X-RAY DIFFRACTIONr_mcangle_other3.3062.386256
X-RAY DIFFRACTIONr_scbond_it5.5512.01229
X-RAY DIFFRACTIONr_scbond_other5.5512.008229
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.9732.958337
X-RAY DIFFRACTIONr_long_range_B_refined10.52619.748429
X-RAY DIFFRACTIONr_long_range_B_other10.51419.775430
X-RAY DIFFRACTIONr_rigid_bond_restr8.6623838
X-RAY DIFFRACTIONr_sphericity_free44.192521
X-RAY DIFFRACTIONr_sphericity_bonded17.5145864
LS refinement shellResolution: 1.333→1.368 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.172 70 -
Rwork0.161 1195 -
obs--94.54 %

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