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- PDB-3p33: Insulin fibrillation is the Janus face of induced fit. A chiral c... -

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Basic information

Entry
Database: PDB / ID: 3p33
TitleInsulin fibrillation is the Janus face of induced fit. A chiral clamp stabilizes the native state at the expense of activity
Components(Insulin) x 2
KeywordsHORMONE / zinc-binding site / long-acting insulin analog / receptor binding protein engineering / global health / insulin fibrillation
Function / homology
Function and homology information


Synthesis, secretion, and deacylation of Ghrelin / Signaling by Insulin receptor / COPI-mediated anterograde transport / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / IRS activation / Signal attenuation / Insulin receptor signalling cascade / Regulation of insulin secretion / Insulin receptor recycling / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes ...Synthesis, secretion, and deacylation of Ghrelin / Signaling by Insulin receptor / COPI-mediated anterograde transport / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / IRS activation / Signal attenuation / Insulin receptor signalling cascade / Regulation of insulin secretion / Insulin receptor recycling / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / Amyloid fiber formation / Insulin processing / Regulation of gene expression in beta cells / negative regulation of glycogen catabolic process / alpha-beta T cell activation / negative regulation of fatty acid metabolic process / negative regulation of NAD(P)H oxidase activity / negative regulation of feeding behavior / positive regulation of respiratory burst / regulation of protein secretion / positive regulation of peptide hormone secretion / negative regulation of respiratory burst involved in inflammatory response / negative regulation of blood vessel diameter / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of dendritic spine maintenance / positive regulation of lipid biosynthetic process / regulation of transmembrane transporter activity / negative regulation of gluconeogenesis / negative regulation of reactive oxygen species biosynthetic process / negative regulation of lipid catabolic process / negative regulation of protein secretion / positive regulation of cellular protein metabolic process / negative regulation of protein oligomerization / fatty acid homeostasis / regulation of protein localization to plasma membrane / positive regulation of glycogen biosynthetic process / positive regulation of nitric oxide mediated signal transduction / regulation of cellular amino acid metabolic process / transport vesicle / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / regulation of synaptic plasticity / endosome lumen / cognition / neuron projection maintenance / positive regulation of insulin receptor signaling pathway / insulin-like growth factor receptor binding / positive regulation of cytokine secretion / positive regulation of protein autophosphorylation / positive regulation of mitotic nuclear division / negative regulation of acute inflammatory response / positive regulation of glycolytic process / positive regulation of cell differentiation / regulation of protein localization / positive regulation of long-term synaptic potentiation / activation of protein kinase B activity / positive regulation of glucose import / positive regulation of blood vessel diameter / negative regulation of protein catabolic process / acute-phase response / hormone activity / positive regulation of nitric-oxide synthase activity / negative regulation of proteolysis / positive regulation of protein localization to nucleus / insulin receptor binding / insulin receptor signaling pathway / glucose metabolic process / cell-cell signaling / Golgi lumen / wound healing / glucose homeostasis / endoplasmic reticulum to Golgi vesicle-mediated transport / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase signaling / positive regulation of cell growth / secretory granule lumen / positive regulation of NF-kappaB transcription factor activity / protease binding / positive regulation of cell migration / positive regulation of protein kinase B signaling / Golgi membrane / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / regulation of transcription, DNA-templated / cellular protein metabolic process / positive regulation of gene expression / positive regulation of cell population proliferation / extracellular space / extracellular region / identical protein binding
Insulin / Insulin-like / Insulin family / Insulin, conserved site / Insulin-like superfamily / Insulin/IGF/Relaxin family / Insulin family signature.
Insulin
Biological speciesHomo Sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsHua, Q.X. / Wan, Z.L. / Huang, K. / Hu, S.Q. / Phillip, N.F. / Jia, W.H. / Whittingham, J. / Dodson, G.G. / Katsoyannis, P.G. / Weiss, M.A.
Citation
Journal: To be Published
Title: Insulin fibrillation is the Janus face of induced fit. A chiral clamp stabilizes the native state at the expense of activity
Authors: Hua, Q.X. / Wan, Z.L. / Huang, K. / Hu, S.Q. / Phillip, N.F. / Jia, W.H. / Whittingham, J. / Dodson, G.G. / Katsoyannis, P.G. / Weiss, M.A.
#1: Journal: Biochemistry / Year: 2005
Title: Diabetes-associated mutations in human insulin: crystal structure and photo-cross-linking studies of a-chain variant insulin Wakayama.
Authors: Wan, Z.L. / Huang, K. / Xu, B. / Hu, S.Q. / Wang, S. / Chu, Y.C. / Katsoyannis, P.G. / Weiss, M.A.
#2: Journal: Biochemistry / Year: 2003
Title: Crystal structure of allo-Ile(A2)-insulin, an inactive chiral analogue: implications for the mechanism of receptor binding
Authors: Wan, Z.L. / Xu, B. / Chu, Y.C. / Katsoyannis, P.G. / Weiss, M.A.
#3: Journal: Biochemistry / Year: 2004
Title: Enhancing the activity of insulin at the receptor interface: crystal structure and photo-cross-linking of A8 analogues.
Authors: Wan, Z.L. / Xu, B. / Chu, Y.C. / Li, B. / Nakagawa, S.H. / Qu, Y. / Hu, S.Q. / Katsoyannis, P.G. / Weiss, M.A.
#4: Journal: Philos.Trans.R.Soc.London,Ser.B / Year: 1988
Title: The structure of 2zn pig insulin crystal at 1.5 A resolution
Authors: Baker, E.N. / Blundell, T.L. / Cutfield, J.F. / Cutfield, S.M. / Dodson, E.J. / Dodson, G.G. / Hodgkin, D. / Isaacs, N.W. / Reynolds, C.D.
#5: Journal: Nature / Year: 1976
Title: Structure of insulin in 4-zinc insulin
Authors: Bentley, G. / Dodson, E. / Dodson, G. / Hodgkin, D. / Mercola, D.
#6: Journal: Nature / Year: 1989
Title: Phenol stabilizes more helix in a new symmetrical zinc insulin hexamer
Authors: Derewenda, U. / Derewenda, Z. / Dodson, E. / Dodson, G. / Reynold, C. / Smith, G. / Sparks, C. / Swenson, D.
Validation Report
SummaryFull reportAbout validation report
History
DepositionOct 4, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 23, 2011Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Oct 15, 2014Group: Derived calculations

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Insulin
B: Insulin
C: Insulin
D: Insulin
E: Insulin
F: Insulin
G: Insulin
H: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,05020
Polymers23,2718
Non-polymers78012
Water1,62190
1
A: Insulin
B: Insulin
hetero molecules

A: Insulin
B: Insulin
hetero molecules

A: Insulin
B: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,03815
Polymers17,4536
Non-polymers5859
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area5610 Å2
ΔGint-154 kcal/mol
Surface area11070 Å2
MethodPISA
2
C: Insulin
D: Insulin
hetero molecules

C: Insulin
D: Insulin
hetero molecules

C: Insulin
D: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,03815
Polymers17,4536
Non-polymers5859
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area5550 Å2
ΔGint-158 kcal/mol
Surface area11510 Å2
MethodPISA
3
E: Insulin
F: Insulin
hetero molecules

E: Insulin
F: Insulin
hetero molecules

E: Insulin
F: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,03815
Polymers17,4536
Non-polymers5859
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area6200 Å2
ΔGint-150 kcal/mol
Surface area10220 Å2
MethodPISA
4
G: Insulin
H: Insulin
hetero molecules

G: Insulin
H: Insulin
hetero molecules

G: Insulin
H: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)18,03815
Polymers17,4536
Non-polymers5859
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area5860 Å2
ΔGint-146 kcal/mol
Surface area10880 Å2
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)77.900, 77.900, 78.300
Angle α, β, γ (deg.)90, 90, 120
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11B-31-

ZN

21B-32-

CL

31D-31-

ZN

41D-32-

CL

51F-31-

ZN

61F-32-

CL

71H-31-

ZN

81H-32-

CL

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Components

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Protein/peptide , 2 types, 8 molecules ACEGBDFH

#1: Protein/peptide
Insulin / / Insulin A chain


Mass: 2383.698 Da / Num. of mol.: 4 / Fragment: unp residues 90-110 / Source method: obtained synthetically / Source: (synth.) Homo Sapiens (human) / References: UniProt: P01308
#2: Protein/peptide
Insulin / / Insulin B chain


Mass: 3433.953 Da / Num. of mol.: 4 / Fragment: unp residues 25-54 / Source method: obtained synthetically / Source: (synth.) Homo Sapiens (human) / References: UniProt: P01308

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Non-polymers , 4 types, 102 molecules

#3: Chemical
ChemComp-IPH / PHENOL


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


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn / Zinc
#5: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl / Chloride
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 90 / Source method: isolated from a natural source / Formula: H2O / Water

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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: 1.96 Å3/Da / Density % sol: 37.4 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8.3
Details: 0.05 M sodium citrate, 1% phenol, 0.04% zinc acetate, pH 8.3, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: BRUKER AXS MICROSTAR / Wavelength: 1.5418 Å
DetectorDate: Jan 14, 2005 / Details: MIRRORS
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.3→51.11 Å / Num. all: 10337 / Num. obs: 10019 / % possible obs: 96.92 % / Redundancy: 4.41 % / Biso Wilson estimate: 31.2 Å2 / Rmerge(I) obs: 0.063 / Net I/σ(I): 7.37
Reflection shellResolution: 2.3→2.44 Å / Redundancy: 4.8 % / Rmerge(I) obs: 0.265 / Mean I/σ(I) obs: 7.7 / Num. unique all: 897 / % possible all: 76.7

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Processing

Software
NameClassification
PROTEUM PLUSdata collection
CNSrefinement
PROTEUM PLUSdata reduction
PROTEUM PLUSdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: pdb entry 1XDA
Resolution: 2.3→51.11 Å / Isotropic thermal model: restrained / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.299 733 -Random
Rwork0.214 ---
All-7872 --
Obs-7098 90.2 %-
Displacement parametersBiso mean: 47.3 Å2
Baniso -1Baniso -2Baniso -3
1-4.14 Å20 Å20 Å2
2--4.14 Å20 Å2
3----8.28 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å / Luzzati d res low obs: 5 Å / Luzzati sigma a obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 2.3→51.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1620 0 36 90 1746
Refine LS restraints
Refinement-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_d0.008
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d19.7
X-RAY DIFFRACTIONc_improper_angle_d0.7
LS refinement shellResolution: 2.3→2.44 Å / Rfactor Rfree error: 0.032
RfactorNum. reflection% reflection
Rfree0.336 113 -
Rwork0.24 --
Obs-897 76.7 %

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