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- PDB-2wru: Semi-synthetic highly active analogue of human insulin NMeAlaB26-... -

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Basic information

Entry
Database: PDB / ID: 2wru
TitleSemi-synthetic highly active analogue of human insulin NMeAlaB26-DTI- NH2
Components
  • INSULIN A CHAIN
  • INSULIN B CHAIN
KeywordsHORMONE / CARBOHYDRATE METABOLISM / GLUCOSE METABOLISM / ANALOGUE / DIABETES MELLITUS
Function / homology
Function and homology information


negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / positive regulation of nitric oxide mediated signal transduction / negative regulation of fatty acid metabolic process / negative regulation of feeding behavior / Signaling by Insulin receptor / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / negative regulation of acute inflammatory response / Regulation of gene expression in beta cells / alpha-beta T cell activation / regulation of amino acid metabolic process / negative regulation of respiratory burst involved in inflammatory response / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of protein secretion / regulation of protein localization to plasma membrane / fatty acid homeostasis / negative regulation of lipid catabolic process / negative regulation of gluconeogenesis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / endosome lumen / negative regulation of proteolysis / positive regulation of D-glucose import / positive regulation of protein secretion / Regulation of insulin secretion / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / negative regulation of protein catabolic process / regulation of synaptic plasticity / hormone activity / positive regulation of neuron projection development / cognition / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / regulation of protein localization / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of cell migration / G protein-coupled receptor signaling pathway / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / negative regulation of gene expression / positive regulation of cell population proliferation / regulation of DNA-templated transcription / positive regulation of gene expression / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily
Similarity search - Domain/homology
ACETATE ION / Insulin
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.57 Å
AuthorsBrzozowski, A.M. / Jiracek, J. / Zakova, L. / Antolikova, E. / Watson, C.J. / Turkenburg, J.P. / Dodson, G.G.
CitationJournal: Proc.Natl.Acad.Sci.USA / Year: 2010
Title: Implications for the Active Form of Human Insulin Based on the Structural Convergence of Highly Active Hormone Analogues.
Authors: Jiracek, J. / Zakova, L. / Antolikova, E. / Watson, C.J. / Turkenburg, J.P. / Dodson, G.G. / Brzozowski, A.M.
History
DepositionSep 2, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 9, 2010Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2013Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Refinement description / Version format compliance
Revision 1.2Mar 20, 2013Group: Derived calculations
Revision 1.3Dec 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)5,4284
Polymers5,3102
Non-polymers1182
Water1,09961
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)10,8568
Polymers10,6204
Non-polymers2364
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_556-y,-x,-z+11
Buried area3760 Å2
ΔGint-38.3 kcal/mol
Surface area5740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)38.721, 38.721, 123.148
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122
Components on special symmetry positions
IDModelComponents
11B-1025-

ACT

21B-1025-

ACT

31A-2028-

HOH

41B-2017-

HOH

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Components

#1: Protein/peptide INSULIN A CHAIN


Mass: 2383.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#2: Protein/peptide INSULIN B CHAIN


Mass: 2926.397 Da / Num. of mol.: 1 / Fragment: RESIDUES 25-50 / Mutation: YES / Source method: obtained synthetically
Details: THIS IS B-CHAIN OF HUMAN INSULIN WITH B26Y MUTATED TO A, TRUNCATED TO POSITION B26 AND TERMINATED WITH CARBOXYAMIDE AT POSITION B26. THE NITROGEN ATOM OF B26 IS METHYLATED.
Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 61 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN B, TYR 50 TO ZZJ
Nonpolymer detailsACETATE (ACT): ACETATE ION
Sequence detailsB26 TYR TO ALA B27-B30 ARE DELETED B26 IS TERMINATED WITH CARBOXYAMIDE B26 N PEPTIDE ATOM IS METHYLATED

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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: 2.3 Å3/Da / Density % sol: 47 % / Description: NONE
Crystal growpH: 3 / Details: 0.32 M NA2SO4, PH 3.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 1.0712
DetectorType: ADSC CCD / Detector: CCD / Date: Dec 3, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0712 Å / Relative weight: 1
ReflectionResolution: 1.57→50 Å / Num. obs: 7028 / % possible obs: 95 % / Observed criterion σ(I): 0 / Redundancy: 10.6 % / Biso Wilson estimate: 20.7 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 23
Reflection shellResolution: 1.57→1.63 Å / Redundancy: 2 % / Rmerge(I) obs: 0.16 / Mean I/σ(I) obs: 11 / % possible all: 61.6

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Processing

Software
NameVersionClassification
REFMAC5.5.0082refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1MSO

1mso


Resolution: 1.57→36.94 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.918 / SU B: 3.534 / SU ML: 0.058 / Cross valid method: THROUGHOUT / ESU R: 0.124 / ESU R Free: 0.108 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES - RESIDUAL ONLY. FOR SIDE CHAINS AND RESIDUES WITH POOR DENSITY THE OCCUPANCY HAS BEEN SET TO ZERO. THE B26TYR IS MUTATED TO ALA. ...Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.U VALUES - RESIDUAL ONLY. FOR SIDE CHAINS AND RESIDUES WITH POOR DENSITY THE OCCUPANCY HAS BEEN SET TO ZERO. THE B26TYR IS MUTATED TO ALA. B27-B30 ARE DELETED. N ATOM OF B26 IS METHYLATED. B26 C-TERMINUS IS CONH2
RfactorNum. reflection% reflectionSelection details
Rfree0.25474 313 4.7 %RANDOM
Rwork0.17873 ---
obs0.18207 6339 95.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 10.588 Å2
Baniso -1Baniso -2Baniso -3
1-0.48 Å20 Å20 Å2
2--0.48 Å20 Å2
3----0.96 Å2
Refinement stepCycle: LAST / Resolution: 1.57→36.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms358 0 8 61 427
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0220.021377
X-RAY DIFFRACTIONr_bond_other_d0.0010.02219
X-RAY DIFFRACTIONr_angle_refined_deg1.7441.968511
X-RAY DIFFRACTIONr_angle_other_deg1.093540
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.304546
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.79225.88217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.1541555
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1170.257
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02429
X-RAY DIFFRACTIONr_gen_planes_other0.0010.0271
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_it1.9611.5242
X-RAY DIFFRACTIONr_mcbond_other0.8191.595
X-RAY DIFFRACTIONr_mcangle_it2.7792377
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it4.0213135
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.7384.5134
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr1.9143596
X-RAY DIFFRACTIONr_sphericity_free9.221367
X-RAY DIFFRACTIONr_sphericity_bonded3.8613590
LS refinement shellResolution: 1.568→1.608 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.434 14 -
Rwork0.26 285 -
obs--60.28 %
Refinement TLS params.Method: refined / Origin x: 8.6096 Å / Origin y: -12.182 Å / Origin z: 54.5959 Å
111213212223313233
T0.028 Å2-0.0276 Å2-0.0205 Å2-0.0687 Å20.0008 Å2--0.0308 Å2
L2.2932 °20.6049 °2-0.6337 °2-0.5436 °2-0.2122 °2--2.4633 °2
S0.0279 Å °-0.0715 Å °-0.0322 Å °0.009 Å °-0.0654 Å °-0.0195 Å °-0.1284 Å °0.115 Å °0.0374 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 21
2X-RAY DIFFRACTION1B2 - 26

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