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- PDB-5hpu: Insulin with proline analog HyP at position B28 in the R6 state -

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Basic information

Entry
Database: PDB / ID: 5hpu
TitleInsulin with proline analog HyP at position B28 in the R6 state
Components(Insulin, chain ...) x 2
KeywordsHORMONE / Insulin / non-canonical amino acid / hydroxyproline / non-natural amino acid / unnatural amino acid
Function / homology
Function and homology information


negative regulation of glycogen catabolic process / Signaling by Insulin receptor / regulation of cellular amino acid metabolic process / IRS activation / negative regulation of NAD(P)H oxidase activity / Insulin processing / nitric oxide-cGMP-mediated signaling pathway / Insulin receptor recycling / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior ...negative regulation of glycogen catabolic process / Signaling by Insulin receptor / regulation of cellular amino acid metabolic process / IRS activation / negative regulation of NAD(P)H oxidase activity / Insulin processing / nitric oxide-cGMP-mediated signaling pathway / Insulin receptor recycling / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / 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 / alpha-beta T cell activation / negative regulation of gluconeogenesis / negative regulation of acute inflammatory response / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of dendritic spine maintenance / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of glycogen biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / negative regulation of protein secretion / Signal attenuation / positive regulation of nitric oxide mediated signal transduction / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of lipid biosynthetic process / negative regulation of lipid catabolic process / fatty acid homeostasis / endosome lumen / positive regulation of insulin receptor signaling pathway / Regulation of insulin secretion / endoplasmic reticulum-Golgi intermediate compartment membrane / transport vesicle / positive regulation of protein autophosphorylation / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of protein metabolic process / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of brown fat cell differentiation / positive regulation of mitotic nuclear division / positive regulation of long-term synaptic potentiation / regulation of transmembrane transporter activity / positive regulation of cell differentiation / regulation of synaptic plasticity / activation of protein kinase B activity / cognition / positive regulation of cytokine production / positive regulation of protein secretion / acute-phase response / positive regulation of glucose import / negative regulation of proteolysis / positive regulation of nitric-oxide synthase activity / hormone activity / insulin receptor binding / vasodilation / negative regulation of protein catabolic process / insulin receptor signaling pathway / positive regulation of protein localization to nucleus / wound healing / Golgi lumen / regulation of protein localization / glucose metabolic process / glucose homeostasis / cell-cell signaling / positive regulation of phosphatidylinositol 3-kinase signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / positive regulation of NF-kappaB transcription factor activity / positive regulation of protein kinase B signaling / positive regulation of MAPK cascade / protease binding / G protein-coupled receptor signaling pathway / positive regulation of cell migration / Amyloid fiber formation / Golgi membrane / negative regulation of gene expression / endoplasmic reticulum lumen / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin / insulin-like growth factor / relaxin family. / Insulin/IGF/Relaxin family / Insulin-like / Insulin family signature. / Insulin-like superfamily / Insulin, conserved site
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.2 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 1.2Nov 22, 2017Group: Structure summary / Category: entity / Item: _entity.pdbx_description
Revision 1.3Jan 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, chain A
B: Insulin, chain B
C: Insulin, chain A
D: Insulin, chain B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,05710
Polymers11,6674
Non-polymers3906
Water30617
1
A: Insulin, chain A
B: Insulin, chain B
C: Insulin, chain A
D: Insulin, chain B
hetero molecules

A: Insulin, chain A
B: Insulin, chain B
C: Insulin, chain A
D: Insulin, chain B
hetero molecules

A: Insulin, chain A
B: Insulin, chain B
C: Insulin, chain A
D: Insulin, chain B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,17230
Polymers35,00212
Non-polymers1,17018
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_645-y+1,x-y-1,z1
crystal symmetry operation3_765-x+y+2,-x+1,z1
Buried area19170 Å2
ΔGint-325 kcal/mol
Surface area11700 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.757, 77.757, 40.397
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11B-101-

ZN

21B-102-

CL

31D-101-

ZN

41D-102-

CL

51B-207-

HOH

61D-204-

HOH

71D-207-

HOH

81D-208-

HOH

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Components

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Insulin, chain ... , 2 types, 4 molecules ACBD

#1: Protein/peptide Insulin, chain A /


Mass: 2383.698 Da / Num. of mol.: 2
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, chain B /


Mass: 3449.953 Da / Num. of mol.: 2
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

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Non-polymers , 4 types, 23 molecules

#3: Chemical ChemComp-IPH / PHENOL / Phenol


Mass: 94.111 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C6H6O
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.07 Å3/Da / Density % sol: 40.57 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 300 mM Tris, 17 mM zinc acetate, 1% phenol, 1.95 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: Aug 3, 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: 2.007→38.879 Å / Num. all: 5892 / Num. obs: 5892 / % possible obs: 97 % / Redundancy: 3 % / Rpim(I) all: 0.041 / Rrim(I) all: 0.076 / Rsym value: 0.063 / Net I/av σ(I): 6.774 / Net I/σ(I): 7.4 / Num. measured all: 17784
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.01-2.122.51.3470.5187.8
2.12-2.243.10.7051198.8
2.24-2.430.4491.5198.6
2.4-2.593.10.2083.4199.3
2.59-2.843.10.1345.1198
2.84-3.1730.0967.2198.5
3.17-3.673.10.06210.1198.7
3.67-4.493.10.04912.8198
4.49-6.353.10.04513.3198.5
6.35-38.8793.20.03515.8197.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
REFMAC5.8.0073refinement
SCALA3.3.21data scaling
PHASER2.5.6phasing
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1EV3
Resolution: 2.2→38.88 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.962 / SU B: 16.246 / SU ML: 0.182 / Cross valid method: THROUGHOUT / ESU R: 0.292 / ESU R Free: 0.21 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21791 253 5.5 %RANDOM
Rwork0.1581 ---
obs0.16123 4307 98.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 65.757 Å2
Baniso -1Baniso -2Baniso -3
1--0.12 Å2-0.06 Å20 Å2
2---0.12 Å20 Å2
3---0.4 Å2
Refinement stepCycle: 1 / Resolution: 2.2→38.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms750 0 18 17 785
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0170.019784
X-RAY DIFFRACTIONr_bond_other_d0.0020.02686
X-RAY DIFFRACTIONr_angle_refined_deg1.8361.9821063
X-RAY DIFFRACTIONr_angle_other_deg0.94831568
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.458593
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.24724.44436
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.33215113
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.494152
X-RAY DIFFRACTIONr_chiral_restr0.1150.2117
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02891
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02199
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_it3.3153.414384
X-RAY DIFFRACTIONr_mcbond_other3.3153.414384
X-RAY DIFFRACTIONr_mcangle_it5.3385.074473
X-RAY DIFFRACTIONr_mcangle_other5.3325.077474
X-RAY DIFFRACTIONr_scbond_it4.1523.901400
X-RAY DIFFRACTIONr_scbond_other4.1483.905401
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.7825.695591
X-RAY DIFFRACTIONr_long_range_B_refined10.06827.648879
X-RAY DIFFRACTIONr_long_range_B_other10.06327.64879
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.2→2.257 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.323 19 -
Rwork0.253 325 -
obs--98.57 %
Refinement TLS params.

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

IDL112)L122)L132)L222)L232)L332)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T112)T122)T132)T222)T232)T332)Origin x (Å)Origin y (Å)Origin z (Å)
16.65926.8271.5517.00321.58590.36960.6486-0.80680.51620.6623-0.82860.48860.1225-0.16010.17990.2075-0.1255-0.13750.283-0.03610.610887.87713.1378.707
23.42940.02840.12561.2005-0.89340.7909-0.0232-0.06440.36860.18940.0679-0.206-0.0684-0.0579-0.04480.2423-0.0219-0.08590.2221-0.00040.496887.5086.0843.171
35.2635-4.3609-1.40913.63251.15930.39690.37670.54150.3504-0.32-0.3857-0.3728-0.0522-0.13270.0090.15420.11410.24720.3435-0.06870.651392.983-5.607-9.219
43.21420.23110.63682.0631-1.97262.1678-0.19430.2265-0.2746-0.00280.1337-0.302-0.0905-0.06760.06060.1712-0.03820.08150.205-0.0140.608688.8710.908-4.377
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 21
2X-RAY DIFFRACTION2B2 - 28
3X-RAY DIFFRACTION3C1 - 21
4X-RAY DIFFRACTION4D1 - 27

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