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- PDB-6s4i: Crystal structure of zinc free A14E, B25H, B29K(N(eps)-[2-(2-[2-(... -

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Basic information

Entry
Database: PDB / ID: 6s4i
TitleCrystal structure of zinc free A14E, B25H, B29K(N(eps)-[2-(2-[2-(2-[2-(Octadecandioyl-gamma-Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]), desB30 human insulin
Components(Insulin) x 2
KeywordsHORMONE / insulin / oral / dimer / zinc free
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 / negative regulation of protein secretion / positive regulation of dendritic spine maintenance / positive regulation of glycogen biosynthetic process / Synthesis, secretion, and deacylation of Ghrelin / regulation of protein localization to plasma membrane / fatty acid homeostasis / negative regulation of gluconeogenesis / negative regulation of lipid catabolic process / 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 / positive regulation of protein autophosphorylation / Insulin receptor recycling / transport vesicle / insulin-like growth factor receptor binding / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / positive regulation of nitric-oxide synthase activity / positive regulation of cytokine production / positive regulation of long-term synaptic potentiation / acute-phase response / endosome lumen / Regulation of insulin secretion / positive regulation of D-glucose import / positive regulation of protein secretion / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin receptor binding / wound healing / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / positive regulation of neuron projection development / cognition / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / cell-cell signaling / insulin receptor signaling pathway / 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
NITRATE ION / Insulin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SAD / Resolution: 1.511 Å
AuthorsJohansson, E.
CitationJournal: Nat Commun / Year: 2020
Title: Molecular engineering of safe and efficacious oral basal insulin.
Authors: Hubalek, F. / Refsgaard, H.H.F. / Gram-Nielsen, S. / Madsen, P. / Nishimura, E. / Munzel, M. / Brand, C.L. / Stidsen, C.E. / Claussen, C.H. / Wulff, E.M. / Pridal, L. / Ribel, U. / ...Authors: Hubalek, F. / Refsgaard, H.H.F. / Gram-Nielsen, S. / Madsen, P. / Nishimura, E. / Munzel, M. / Brand, C.L. / Stidsen, C.E. / Claussen, C.H. / Wulff, E.M. / Pridal, L. / Ribel, U. / Kildegaard, J. / Porsgaard, T. / Johansson, E. / Steensgaard, D.B. / Hovgaard, L. / Glendorf, T. / Hansen, B.F. / Jensen, M.K. / Nielsen, P.K. / Ludvigsen, S. / Rugh, S. / Garibay, P.W. / Moore, M.C. / Cherrington, A.D. / Kjeldsen, T.
History
DepositionJun 28, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 15, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _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 / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Insulin
B: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)5,7974
Polymers5,6732
Non-polymers1242
Water57632
1
A: Insulin
B: Insulin
hetero molecules

A: Insulin
B: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,5958
Polymers11,3474
Non-polymers2484
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation16_565x,-y+1,-z+1/21
Unit cell
Length a, b, c (Å)77.482, 77.482, 77.482
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number199
Space group name H-MI213

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Components

#1: Protein/peptide Insulin


Mass: 2349.638 Da / Num. of mol.: 1 / Mutation: Y14E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
#2: Protein/peptide Insulin


Mass: 3323.822 Da / Num. of mol.: 1 / Mutation: F25H,des30
Source method: isolated from a genetically manipulated source
Details: Insulin B chain LYS B29 CHEMICALLY MODIFIED WITH [2-(2-[2-(2-[2-(Octadecandioyl-gamma-Glu)amino]ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]
Source: (gene. exp.) Homo sapiens (human) / Gene: INS / Production host: Saccharomyces cerevisiae (brewer's yeast) / References: UniProt: P01308
#3: Chemical ChemComp-NO3 / NITRATE ION


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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 %
Crystal growTemperature: 310 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: Protein solution: 25 mg/ml insulin added 0.1% (w/v) NVoy Precipitant: 6.0 M ammonium nitrate, 0.1 M Tris pH 8.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.548 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: Oct 12, 2009
RadiationProtocol: MAD / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.548 Å / Relative weight: 1
ReflectionResolution: 1.511→31.63 Å / Num. obs: 12258 / % possible obs: 99.7 % / Redundancy: 25.2 % / Biso Wilson estimate: 26.66 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.05816 / Rpim(I) all: 0.009455 / Rrim(I) all: 0.05896 / Net I/σ(I): 54.75
Reflection shellResolution: 1.511→1.565 Å / Redundancy: 14.9 % / Rmerge(I) obs: 0.5101 / Mean I/σ(I) obs: 4.25 / Num. unique obs: 1201 / CC1/2: 0.923 / Rpim(I) all: 0.1337 / Rrim(I) all: 0.5285 / % possible all: 97.4

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Processing

Software
NameVersionClassification
PHENIX(1.15_3448: ???)refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHENIXphasing
RefinementMethod to determine structure: SAD / Resolution: 1.511→31.63 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 21.05
RfactorNum. reflection% reflection
Rfree0.2119 1173 5 %
Rwork0.1803 --
obs0.1818 12255 99.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 40.03 Å2
Refinement stepCycle: LAST / Resolution: 1.511→31.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms376 0 8 32 416
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01435
X-RAY DIFFRACTIONf_angle_d1.065594
X-RAY DIFFRACTIONf_dihedral_angle_d3.277333
X-RAY DIFFRACTIONf_chiral_restr0.05264
X-RAY DIFFRACTIONf_plane_restr0.00783
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5109-1.57960.1951460.21992676X-RAY DIFFRACTION96
1.5796-1.66290.18841420.19072833X-RAY DIFFRACTION100
1.6629-1.76710.21651470.18422808X-RAY DIFFRACTION100
1.7671-1.90350.21851420.18212784X-RAY DIFFRACTION100
1.9035-2.0950.18111480.16892822X-RAY DIFFRACTION100
2.095-2.39810.20581520.16932796X-RAY DIFFRACTION100
2.3981-3.02090.19121400.17782785X-RAY DIFFRACTION100
3.0209-31.63880.22921560.18372793X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 20.629 Å / Origin y: 38.6419 Å / Origin z: 28.2937 Å
111213212223313233
T0.3091 Å2-0.0001 Å20.056 Å2-0.2348 Å20.0393 Å2--0.2387 Å2
L2.5739 °20.0951 °2-1.2618 °2-4.0544 °2-0.5859 °2--5.4494 °2
S0.1326 Å °-0.1039 Å °0.11 Å °0.5433 Å °0.0956 Å °0.3196 Å °-0.0857 Å °-0.027 Å °-0.1865 Å °
Refinement TLS groupSelection details: all

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