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- PDB-3bxq: The structure of a mutant insulin uncouples receptor binding from... -

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Basic information

Entry
Database: PDB / ID: 3bxq
TitleThe structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition
Components
  • insulin A chain
  • insulin B chain
KeywordsHORMONE / TR transition / Electrostatic block / Protein allostery / Receptor binding
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 cellular amino acid metabolic process / 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 / negative regulation of gluconeogenesis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / COPI-mediated anterograde transport / positive regulation of lipid biosynthetic process / negative regulation of reactive oxygen species biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / positive regulation of insulin receptor signaling pathway / nitric oxide-cGMP-mediated signaling / transport vesicle / positive regulation of protein autophosphorylation / Insulin receptor recycling / insulin-like growth factor receptor binding / neuron projection maintenance / NPAS4 regulates expression of target genes / positive regulation of protein metabolic process / positive regulation of brown fat cell differentiation / activation of protein kinase B activity / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of glycolytic process / 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 / negative regulation of protein catabolic process / endosome lumen / positive regulation of 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 / vasodilation / hormone activity / cognition / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / glucose metabolic process / regulation of protein localization / glucose homeostasis / insulin receptor signaling pathway / cell-cell signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / positive regulation of NF-kappaB transcription factor activity / 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 / Golgi membrane / endoplasmic reticulum lumen / 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: 1.3 Å
AuthorsWan, Z.L. / Huang, K. / Hu, S.Q. / Whittaker, J. / Weiss, M.A.
Citation
Journal: J.Biol.Chem. / Year: 2008
Title: The structure of a mutant insulin uncouples receptor binding from protein allostery. An electrostatic block to the TR transition.
Authors: Wan, Z.L. / Huang, K. / Hu, S.Q. / Whittaker, J. / Weiss, M.A.
#1: Journal: J.Biol.Chem. / Year: 2008
Title: Design of an active ultrastable single-chain insulin analog: synthesis, structure, and therapeutic implications.
Authors: Hua, Q.X. / Nakagawa, S.H. / Jia, W. / Huang, K. / Phillips, N.B. / Hu, S.Q. / Weiss, M.A.
#2: 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. / Blujdell, T.L. / Cutfield, J.F. / Cutfield, S.M. / Dodson, E.J. / Dodson, G.G. / Hodgkin, D. / Isaacs, N.W. / Reynolds, C.D.
#3: Journal: Nature / Year: 1976
Title: Structure of insulin in 4-zinc insulin
Authors: Bentley, G. / Dodson, E. / Dodson, G. / Hodgkin, D. / Mercola, D.
#4: 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.
#5: Journal: J.Biol.Chem. / Year: 2006
Title: Toward the active conformation of insulin: stereospecific modulation of a structural swith in the B chain
Authors: Hua, Q.X. / Nakagawa, S. / Hu, S.Q. / Jia, W. / Wang, S. / Weiss, M.A.
History
DepositionJan 14, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2008Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Oct 20, 2021Group: Database references / Derived calculations
Category: database_2 / struct_conn ...database_2 / 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_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_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Apr 13, 2022Group: Database references / Category: citation / citation_author
Revision 1.4Aug 30, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)11,8046
Polymers11,6734
Non-polymers1312
Water2,288127
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)35,41318
Polymers35,02012
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 area12160 Å2
ΔGint-254.9 kcal/mol
Surface area20310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.390, 81.390, 34.000
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

31B-102-

HOH

41B-103-

HOH

51D-103-

HOH

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Components

#1: Protein/peptide insulin A chain


Mass: 2383.698 Da / Num. of mol.: 2 / Source method: obtained synthetically / References: UniProt: P01308
#2: Protein/peptide insulin B chain


Mass: 3453.000 Da / Num. of mol.: 2 / Mutation: R29H / Source method: obtained synthetically / 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


Mass: 18.015 Da / Num. of mol.: 127 / 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: 1.86 Å3/Da / Density % sol: 33.75 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / 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, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 4.2.2 / Wavelength: 1.033 Å
DetectorDetector: CCD / Date: Sep 21, 2006 / Details: mirros
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.3→30.62 Å / Num. all: 40193 / Num. obs: 39411 / % possible obs: 95.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.11 % / Biso Wilson estimate: 13.9 Å2 / Rmerge(I) obs: 0.04 / Net I/σ(I): 21.2
Reflection shellResolution: 1.3→1.38 Å / Redundancy: 2.89 % / Rmerge(I) obs: 0.132 / Mean I/σ(I) obs: 10 / Num. unique all: 4876 / % possible all: 77.9

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Processing

Software
NameClassification
HKL-2000data collection
CNSrefinement
d*TREKdata reduction
d*TREKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4INS

4ins


Resolution: 1.3→30.62 Å / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.232 3817 -random
Rwork0.206 ---
all-20156 --
obs-20156 95.4 %-
Displacement parametersBiso mean: 18.3 Å2
Baniso -1Baniso -2Baniso -3
1-0.13 Å20.39 Å20 Å2
2--0.13 Å20 Å2
3----0.25 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å / Luzzati d res low obs: 5 Å / Luzzati sigma a obs: 0.07 Å
Refinement stepCycle: LAST / Resolution: 1.3→30.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1594 0 2 127 1723
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_d0.17
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d21
X-RAY DIFFRACTIONc_improper_angle_d0.64
LS refinement shellResolution: 1.3→1.38 Å / Rfactor Rfree error: 0.013
RfactorNum. reflection% reflection
Rfree0.262 485 -
Rwork0.239 --
obs-4876 77.9 %

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