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- PDB-2wrv: Semi-synthetic highly active analogue of human insulin NMeHisB26-... -

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Basic information

Entry
Database: PDB / ID: 2wrv
TitleSemi-synthetic highly active analogue of human insulin NMeHisB26-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 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 / regulation of protein secretion / Insulin processing / positive regulation of peptide hormone secretion / positive regulation of respiratory burst ...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 / regulation of protein secretion / Insulin processing / 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 / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / activation of protein kinase B activity / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of insulin receptor signaling pathway / positive regulation of glycogen biosynthetic process / fatty acid homeostasis / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of lipid catabolic process / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / regulation of protein localization to plasma membrane / nitric oxide-cGMP-mediated signaling / transport vesicle / COPI-mediated anterograde transport / positive regulation of nitric-oxide synthase activity / Insulin receptor recycling / negative regulation of reactive oxygen species biosynthetic process / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / positive regulation of glycolytic process / positive regulation of cytokine production / endosome lumen / positive regulation of long-term synaptic potentiation / acute-phase response / positive regulation of protein secretion / positive regulation of D-glucose import / insulin receptor binding / positive regulation of cell differentiation / Regulation of insulin secretion / wound healing / positive regulation of neuron projection development / hormone activity / negative regulation of protein catabolic process / regulation of synaptic plasticity / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / cognition / glucose metabolic process / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / protease binding / secretory granule lumen / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / positive regulation of cell migration / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / Amyloid fiber formation / Golgi membrane / negative regulation of gene expression / 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-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: 2.15 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 1.1Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.2Jun 6, 2012Group: Other
Revision 1.3Aug 30, 2017Group: Data collection / Refinement description
Category: diffrn_detector / refine ...diffrn_detector / refine / reflns / reflns_shell
Item: _diffrn_detector.type / _refine.ls_R_factor_R_free ..._diffrn_detector.type / _refine.ls_R_factor_R_free / _reflns.d_resolution_low / _reflns_shell.Rmerge_I_obs
Revision 1.4Dec 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)5,4353
Polymers5,3762
Non-polymers591
Water81145
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)10,8706
Polymers10,7524
Non-polymers1182
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_454-x-1/2,y,-z-1/41
Buried area3790 Å2
ΔGint-32.1 kcal/mol
Surface area5800 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.170, 39.170, 123.593
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number98
Space group name H-MI4122

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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: 2992.458 Da / Num. of mol.: 1 / Fragment: RESIDUES 25-50 / Mutation: YES / Source method: obtained synthetically / Source: (synth.) HOMO SAPIENS (human) / References: UniProt: P01308
#3: Chemical ChemComp-ACT / ACETATE ION


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / Source method: isolated from a natural source / Formula: H2O
Compound detailsENGINEERED RESIDUE IN CHAIN B, TYR 50 TO HS9
Sequence detailsB26 TYR MUTATED TO HIS, N ATOM OF B26 PEPTIDE IS METHYLATED, B27-B30 ARE DELETED, B26 C-TERMINUS IS ...B26 TYR MUTATED TO HIS, N ATOM OF B26 PEPTIDE IS METHYLATED, B27-B30 ARE DELETED, B26 C-TERMINUS IS FINISHED WITH CONH2 (CARBOXYAMIDE) NOT A COOH GROUP

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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: 43 % / Description: NONE
Crystal growpH: 8.2
Details: 0.1 NA CITRATE, 0.3 M TRIS PH 8.2, 0.6 MM ZN ACETATE, 0.06% PHENOL

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC QUANTUM 4r / Detector: CCD / Date: Feb 19, 2009
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.15→37.34 Å / Num. obs: 4113 / % possible obs: 97.8 % / Observed criterion σ(I): 0 / Redundancy: 7.2 % / Biso Wilson estimate: 24.7 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 14.5
Reflection shellResolution: 2.15→2.19 Å / Redundancy: 7 % / Rmerge(I) obs: 0.269 / Mean I/σ(I) obs: 6.8 / % possible all: 97.4

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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: 2.15→37.34 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.911 / SU B: 13.073 / SU ML: 0.147 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.277 / ESU R Free: 0.239 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. U VALUES RESIDUAL
RfactorNum. reflection% reflectionSelection details
Rfree0.277 126 4.5 %RANDOM
Rwork0.19951 ---
obs0.20298 2686 97.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 16.638 Å2
Baniso -1Baniso -2Baniso -3
1-0.1 Å20 Å20 Å2
2--0.1 Å20 Å2
3----0.2 Å2
Refinement stepCycle: LAST / Resolution: 2.15→37.34 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms363 0 4 45 412
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.021374
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6771.946506
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.273544
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.25324.73719
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.4251558
X-RAY DIFFRACTIONr_dihedral_angle_4_deg5.317151
X-RAY DIFFRACTIONr_chiral_restr0.1350.255
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.02289
X-RAY DIFFRACTIONr_gen_planes_other
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_it1.021.5229
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.8352362
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8123145
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.4224.5144
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.153→2.208 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.394 8 -
Rwork0.219 195 -
obs--97.6 %
Refinement TLS params.Method: refined / Origin x: -10.4859 Å / Origin y: 7.2819 Å / Origin z: -7.1897 Å
111213212223313233
T0.0252 Å2-0.0129 Å20.0017 Å2-0.025 Å20.003 Å2--0.0249 Å2
L1.3326 °20.37 °20.0803 °2-0.7513 °20.356 °2--2.2624 °2
S0.1523 Å °-0.1018 Å °-0.0128 Å °0.0046 Å °-0.1075 Å °-0.0014 Å °-0.1193 Å °0.0686 Å °-0.0448 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1 - 21
2X-RAY DIFFRACTION1B2 - 26

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