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- PDB-6ck2: Insulin analog containing a YB26W mutation -

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Basic information

Entry
Database: PDB / ID: 6ck2
TitleInsulin analog containing a YB26W mutation
Components
  • Insulin A chain
  • Insulin B chain
KeywordsHORMONE / Long-acting / Basal / Therapeutic / Peptide Hormone / Diabetes / Biomolecular Engineering
Function / homology
Function and homology information


negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic 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 ...negative regulation of NAD(P)H oxidase activity / negative regulation of glycogen catabolic process / regulation of cellular amino acid metabolic 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 respiratory burst / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / alpha-beta T cell activation / 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 / Signal attenuation / negative regulation of lipid catabolic process / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / negative regulation of reactive oxygen species biosynthetic process / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / neuron projection maintenance / positive regulation of protein metabolic process / NPAS4 regulates expression of target genes / positive regulation of brown fat cell differentiation / positive regulation of glycolytic process / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / 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 / Regulation of insulin secretion / endosome lumen / positive regulation of protein secretion / positive regulation of glucose import / negative regulation of proteolysis / positive regulation of cell differentiation / regulation of transmembrane transporter activity / insulin-like growth factor receptor binding / wound healing / insulin receptor binding / regulation of synaptic plasticity / negative regulation of protein catabolic process / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / vasodilation / glucose metabolic process / regulation of protein localization / insulin receptor signaling pathway / cell-cell signaling / glucose homeostasis / positive regulation of NF-kappaB transcription factor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of cell growth / secretory granule lumen / protease binding / 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 / positive regulation of gene expression / regulation of DNA-templated transcription / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Insulin / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin-like superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.25 Å
AuthorsRege, N.K. / Yee, V.C. / Weiss, M.A.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK0409849 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)1F30DK112644 United States
CitationJournal: J. Biol. Chem. / Year: 2018
Title: Structure-based stabilization of insulin as a therapeutic protein assembly via enhanced aromatic-aromatic interactions.
Authors: Rege, N.K. / Wickramasinghe, N.P. / Tustan, A.N. / Phillips, N.F.B. / Yee, V.C. / Ismail-Beigi, F. / Weiss, M.A.
History
DepositionFeb 27, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 13, 2018Provider: repository / Type: Initial release
Revision 1.1Jun 27, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.pdbx_database_id_DOI ..._citation.journal_abbrev / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jul 25, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title
Revision 1.3Dec 25, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_conn_type
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn.ptnr2_symmetry / _struct_conn_type.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
C: Insulin A chain
D: Insulin B chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9128
Polymers11,6514
Non-polymers2604
Water72140
1
A: Insulin A chain
B: Insulin B chain
C: Insulin A chain
D: Insulin B chain
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)35,73524
Polymers34,95412
Non-polymers78112
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_765-y+2,x-y+1,z1
crystal symmetry operation3_675-x+y+1,-x+2,z1
Buried area18230 Å2
ΔGint-282 kcal/mol
Surface area12080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)79.755, 79.755, 37.610
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

21D-101-

ZN

31D-102-

CL

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Components

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Protein/peptide , 2 types, 4 molecules ACBD

#1: Protein/peptide Insulin A chain


Mass: 2383.698 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
#2: Protein/peptide Insulin B chain


Mass: 3441.955 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308

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Non-polymers , 4 types, 44 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-IPH / PHENOL


Mass: 94.111 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H6O
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 40 / 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: 1.98 Å3/Da / Density % sol: 37.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: Crystals were obtained by hanging-drop vapor diffusion at room temperature in the presence of a 1:1.7 ratio of Zn2+ to protein monomer and a 3.5:1 ratio of phenol to protein monomer in Tris-HCl
PH range: 7.8-9.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL7-1 / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: May 12, 2016
RadiationMonochromator: Side scattering I-beam bent single crystal; asymmetric cut 4.9650 deg.
Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.25→33.04 Å / Num. obs: 4273 / % possible obs: 99.5 % / Redundancy: 10.1 % / Rmerge(I) obs: 0.03698 / Net I/σ(I): 45.78
Reflection shellResolution: 2.25→2.5755 Å / Redundancy: 9.6 % / Rmerge(I) obs: 0.1028 / Mean I/σ(I) obs: 8.99 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(1.10.1_2155)refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4E7U

4e7u


Resolution: 2.25→33.031 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 26.74
RfactorNum. reflection% reflectionSelection details
Rfree0.2469 395 9.34 %Random Selection
Rwork0.2066 ---
obs0.2103 4230 99.55 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 2.25→33.031 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms778 0 10 40 828
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.011839
X-RAY DIFFRACTIONf_angle_d1.0181145
X-RAY DIFFRACTIONf_dihedral_angle_d16.288493
X-RAY DIFFRACTIONf_chiral_restr0.041123
X-RAY DIFFRACTIONf_plane_restr0.01146
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.25-2.57550.31571370.24281268X-RAY DIFFRACTION99
2.5755-3.24440.2611220.23651295X-RAY DIFFRACTION100
3.2444-33.03410.21381360.17641272X-RAY DIFFRACTION100

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