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- PDB-3fq9: Design of an insulin analog with enhanced receptor-binding select... -

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Basic information

Entry
Database: PDB / ID: 3fq9
TitleDesign of an insulin analog with enhanced receptor-binding selectivity. Rationale, structure, and therapeutic implications
Components(Insulin) x 2
KeywordsHORMONE / receptor-binding / insulin design / rational / therapeutic implication / Carbohydrate metabolism / Cleavage on pair of basic residues / Diabetes mellitus / Disease mutation / Glucose metabolism / Pharmaceutical / Secreted
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
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsZhao, M. / Wan, Z.L. / Whittaker, L. / Xu, B. / Phillips, N. / Katsoyannis, P. / Whittaker, J. / Weiss, M.A.
Citation
Journal: J.Biol.Chem. / Year: 2009
Title: Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications.
Authors: Zhao, M. / Wan, Z.L. / Whittaker, L. / Xu, B. / Phillips, N.B. / Katsoyannis, P.G. / Ismail-Beigi, F. / Whittaker, J. / Weiss, M.A.
#1: 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.
#2: Journal: Nature / Year: 1976
Title: Structure of insulin 4-zinc insulin
Authors: Bentley, G. / Dodson, E. / Dodson, G. / Hodgkin, D. / Mercola, D.
#3: Journal: Nature / Year: 1989
Title: Phenol stabilizes more helix in a new symmetrical zinc insulin hexamer
Authors: Derewenda, U. / Derewenda, Z. / Dodson, G. / Reynold, C. / Smith, G. / Sparks, C. / Swenson, D.
#4: Journal: J.Biol.Chem. / Year: 2006
Title: tpward the active conformation of insulin: stereospecific modelation of a structural swith in the B chain
Authors: Hua, Q. / Nakagawa, S. / Hu, S.Q. / Jia, W. / Wang, S. / Weiss, M.A.
History
DepositionJan 7, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 4, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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_leaving_atom_flag / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)11,7926
Polymers11,6614
Non-polymers1312
Water2,198122
1
A: Insulin
B: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)5,8963
Polymers5,8312
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1700 Å2
ΔGint-16 kcal/mol
Surface area3670 Å2
MethodPISA
2
C: Insulin
D: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)5,8963
Polymers5,8312
Non-polymers651
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1720 Å2
ΔGint-16 kcal/mol
Surface area3620 Å2
MethodPISA
3


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4780 Å2
ΔGint-40 kcal/mol
Surface area5940 Å2
MethodPISA
4
A: Insulin
B: Insulin
hetero molecules

C: Insulin
D: Insulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7926
Polymers11,6614
Non-polymers1312
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
Buried area5050 Å2
ΔGint-46 kcal/mol
Surface area5670 Å2
MethodPISA
5
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)35,37718
Polymers34,98412
Non-polymers3926
Water21612
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-y,x-y,z1
crystal symmetry operation3_555-x+y,-x,z1
Buried area20250 Å2
ΔGint-261 kcal/mol
Surface area12100 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.841, 81.841, 33.518
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-102-

ZN

31D-31-

HOH

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Components

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


Mass: 2396.739 Da / Num. of mol.: 2 / Mutation: A1 is DAL, A8 is DAB / Source method: obtained synthetically
Details: biosynthetic sequence based on Human Insulin A chain
References: UniProt: P01308
#2: Protein/peptide Insulin / / Insulin B chain


Mass: 3433.953 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: biosynthetic sequence based on Human Insulin B chain
References: UniProt: P01308
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 122 / 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: 1.85 Å3/Da / Density % sol: 33.6 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.8
Details: 0.02M Tris, o.o5M soduim citrate, 5%acetone,0.03% phenol,0.01% zinc acetone, pH 7.8, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CHESS / Beamline: F2 / Wavelength: 0.948 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: May 26, 2001 / Details: mirrors
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.948 Å / Relative weight: 1
ReflectionResolution: 1.35→40.92 Å / Num. all: 18393 / Num. obs: 18052 / % possible obs: 98.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Biso Wilson estimate: 13.7 Å2 / Rmerge(I) obs: 0.039 / Net I/σ(I): 20.2
Reflection shellResolution: 1.35→1.43 Å / Redundancy: 2.88 % / Rmerge(I) obs: 0.123 / Mean I/σ(I) obs: 9.9 / Num. unique all: 2571 / % possible all: 93

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Processing

Software
NameVersionClassification
ADSCQuantumdata collection
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4INS

4ins


Resolution: 1.35→40.92 Å / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.228 1729 -RANDOM
Rwork0.198 ---
all-21318 --
obs-18052 98.1 %-
Displacement parametersBiso mean: 18 Å2
Baniso -1Baniso -2Baniso -3
1--1.06 Å20 Å20 Å2
2---1.06 Å20 Å2
3---2.11 Å2
Refine analyzeLuzzati coordinate error obs: 0.16 Å / Luzzati d res low obs: 5 Å / Luzzati sigma a obs: 0.1 Å
Refinement stepCycle: LAST / Resolution: 1.35→40.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1601 0 2 122 1725
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d19.7
X-RAY DIFFRACTIONc_improper_angle_d5.21
LS refinement shellResolution: 1.35→1.43 Å / Rfactor Rfree error: 0.015
RfactorNum. reflection% reflection
Rfree0.265 271 -
Rwork0.245 --
obs-2571 93 %

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