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- PDB-3v19: Forestalling insulin fibrillation by insertion of a chiral clamp ... -

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Basic information

Entry
Database: PDB / ID: 3v19
TitleForestalling insulin fibrillation by insertion of a chiral clamp mechanism-based application of protein engineering to global health
Components(Insulin) x 2
KeywordsHORMONE / zinc-binding site / long-acting insulin analog / receptor binding / protein engineering / insulin fibrillation
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 / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / 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 / Signaling by Insulin receptor / IRS activation / nitric oxide-cGMP-mediated signaling / negative regulation of fatty acid metabolic process / Insulin processing / negative regulation of feeding behavior / regulation of protein secretion / positive regulation of peptide hormone secretion / Regulation of gene expression in beta cells / positive regulation of respiratory burst / positive regulation of dendritic spine maintenance / alpha-beta T cell activation / negative regulation of acute inflammatory response / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / fatty acid homeostasis / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of glycogen biosynthetic process / positive regulation of lipid biosynthetic process / Signal attenuation / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / negative regulation of gluconeogenesis / positive regulation of nitric oxide mediated signal transduction / regulation of protein localization to plasma membrane / COPI-mediated anterograde transport / negative regulation of lipid catabolic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / negative regulation of reactive oxygen species biosynthetic process / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / Regulation of insulin secretion / positive regulation of nitric-oxide synthase activity / positive regulation of long-term synaptic potentiation / endosome lumen / positive regulation of cytokine production / acute-phase response / positive regulation of protein secretion / regulation of transmembrane transporter activity / positive regulation of cell differentiation / positive regulation of glucose import / negative regulation of proteolysis / regulation of synaptic plasticity / wound healing / insulin receptor binding / negative regulation of protein catabolic process / positive regulation of neuron projection development / hormone activity / cognition / Golgi lumen / vasodilation / positive regulation of protein localization to nucleus / glucose metabolic process / regulation of protein localization / glucose homeostasis / cell-cell signaling / insulin receptor signaling pathway / 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 Å
AuthorsWan, Z.L. / Hua, Q.X. / Wickramasinghe, N.P. / Huang, K. / Petkova, A.T. / Hu, S.Q. / Phillips, N.B. / Yeh, I.J. / Whittake, J. / Ismail-Beigi, F. ...Wan, Z.L. / Hua, Q.X. / Wickramasinghe, N.P. / Huang, K. / Petkova, A.T. / Hu, S.Q. / Phillips, N.B. / Yeh, I.J. / Whittake, J. / Ismail-Beigi, F. / Katsoyyannis, P.G. / Tycko, R. / Weiss, M.A.
Citation
Journal: To be Published
Title: Forestalling insulin fibrillation by insertion of a chiral clamp mechanism-based application of protein engineering to global health
Authors: Wan, Z.L. / Hua, Q.X. / Wickramasinghe, N.P. / Huang, K. / Petkova, A.T. / Hu, S.Q. / Phillips, N.B. / Yeh, I.J. / Whittake, J. / Ismail-Beigi, F. / Katsoyyannis, P.G. / Tycko, R. / 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: L Wan, Z. / 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.
History
DepositionDec 9, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 12, 2012Provider: repository / Type: Initial release
Revision 1.1Sep 13, 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_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_ref_seq_dif.details / _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
B: Insulin
C: Insulin
D: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,0339
Polymers11,7374
Non-polymers2965
Water1,18966
1
A: Insulin
B: Insulin
C: Insulin
D: Insulin
hetero molecules

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

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


Theoretical massNumber of molelcules
Total (without water)36,10027
Polymers35,21212
Non-polymers88815
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-y+1,x-y,z1
crystal symmetry operation3_665-x+y+1,-x+1,z1
Buried area19640 Å2
ΔGint-316 kcal/mol
Surface area13140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)78.301, 78.301, 36.224
Angle α, β, γ (deg.)90, 90, 120
Int Tables number146
Space group name H-MH3
Components on special symmetry positions
IDModelComponents
11B-101-

ZN

21B-102-

CL

31D-201-

ZN

41D-202-

CL

51B-31-

HOH

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Components

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Protein/peptide , 2 types, 4 molecules ACBD

#1: Protein/peptide Insulin /


Mass: 2434.768 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P01308
#2: Protein/peptide Insulin /


Mass: 3433.953 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, 71 molecules

#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical ChemComp-IPH / PHENOL / Phenol


Mass: 94.111 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H6O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 66 / 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: 1.82 Å3/Da / Density % sol: 32.44 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8
Details: 0.02 M Tris, 0.05 M sodium citrate, 5% acetone, 0.03% phenol, 0.01% zinc acetate, pH 8.0, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 14-BM-C / Wavelength: 0.9002 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 8, 2007 / Details: Si 111
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9002 Å / Relative weight: 1
ReflectionResolution: 2→16.69 Å / Num. all: 5596 / Num. obs: 5515 / % possible obs: 98.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.2 % / Biso Wilson estimate: 21.6 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 43.5
Reflection shellResolution: 2→2.07 Å / Redundancy: 5.1 % / Rmerge(I) obs: 0.315 / Mean I/σ(I) obs: 6.57 / Num. unique all: 798 / % possible all: 100

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNSrefinement
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RWE

1rwe


Resolution: 2→16.69 Å / Isotropic thermal model: restrained / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.266 574 -Random
Rwork0.208 ---
all-5596 --
obs-5371 96.1 %-
Displacement parametersBiso mean: 42.7 Å2
Baniso -1Baniso -2Baniso -3
1-2.36 Å20 Å20 Å2
2--2.36 Å20 Å2
3----4.73 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å / Luzzati d res low obs: 5 Å / Luzzati sigma a obs: 0.18 Å
Refinement stepCycle: LAST / Resolution: 2→16.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms818 0 11 66 895
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_d0.008
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_dihedral_angle_d20.6
X-RAY DIFFRACTIONc_improper_angle_d0.62
LS refinement shellResolution: 2→2.13 Å / Rfactor Rfree error: 0.034
RfactorNum. reflection% reflection
Rfree0.326 98 -
Rwork0.259 --
obs-798 95.2 %

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