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- PDB-1jca: Non-standard Design of Unstable Insulin Analogues with Enhanced A... -

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Basic information

Entry
Database: PDB / ID: 1jca
TitleNon-standard Design of Unstable Insulin Analogues with Enhanced Activity
Components
  • insulin a
  • insulin b
KeywordsHORMONE/GROWTH FACTOR / A8-Lysine human insulin / insulin receptor / HORMONE-GROWTH FACTOR COMPLEX
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 / Signaling by Insulin receptor / negative regulation of feeding behavior / 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 / Signaling by Insulin receptor / negative regulation of feeding behavior / IRS activation / Insulin processing / regulation of protein secretion / positive regulation of peptide hormone secretion / positive regulation of respiratory burst / Regulation of gene expression in beta cells / negative regulation of acute inflammatory response / positive regulation of protein autophosphorylation / alpha-beta T cell activation / positive regulation of dendritic spine maintenance / Synthesis, secretion, and deacylation of Ghrelin / negative regulation of respiratory burst involved in inflammatory response / negative regulation of protein secretion / negative regulation of gluconeogenesis / positive regulation of glycogen biosynthetic process / Signal attenuation / fatty acid homeostasis / FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes / positive regulation of insulin receptor signaling pathway / negative regulation of lipid catabolic process / regulation of protein localization to plasma membrane / positive regulation of lipid biosynthetic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / activation of protein kinase B activity / COPI-mediated anterograde transport / transport vesicle / nitric oxide-cGMP-mediated signaling / negative regulation of reactive oxygen species biosynthetic process / Insulin receptor recycling / insulin-like growth factor receptor binding / positive regulation of brown fat cell differentiation / NPAS4 regulates expression of target genes / neuron projection maintenance / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of nitric-oxide synthase activity / positive regulation of mitotic nuclear division / Insulin receptor signalling cascade / regulation of transmembrane transporter activity / positive regulation of glycolytic process / positive regulation of long-term synaptic potentiation / positive regulation of cytokine production / endosome lumen / acute-phase response / positive regulation of D-glucose import / positive regulation of protein secretion / positive regulation of cell differentiation / Regulation of insulin secretion / insulin receptor binding / wound healing / negative regulation of protein catabolic process / hormone activity / regulation of synaptic plasticity / positive regulation of neuron projection development / positive regulation of protein localization to nucleus / Golgi lumen / cognition / glucose metabolic process / vasodilation / insulin receptor signaling pathway / glucose homeostasis / cell-cell signaling / regulation of protein localization / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protease binding / positive regulation of cell growth / secretory granule lumen / positive regulation of canonical NF-kappaB signal transduction / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of MAPK cascade / 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-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / Insulin-like superfamily
Similarity search - Domain/homology
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.5 Å
AuthorsWeiss, M.A. / Wan, Z. / Zhao, M. / Chu, Y.-C. / Nakagawa, S.H. / Burke, G.T. / Jia, W. / Hellmich, R. / Katsoyannis, P.G.
Citation
Journal: J.Mol.Biol. / Year: 2002
Title: Non-standard insulin design: structure-activity relationships at the periphery of the insulin receptor.
Authors: Weiss, M.A. / Wan, Z. / Zhao, M. / Chu, Y.C. / Nakagawa, S.H. / Burke, G.T. / Jia, W. / Hellmich, R. / Katsoyannis, P.G.
#1: Journal: BIOPHYS.CHEM. / Year: 1994
Title: A Proposed Interaction Model of Insulin Molecules with its Receptor
Authors: Liang, D.C. / Chang, W.R. / Wan, Z.L. / Vijayan, N.M.
#2: Journal: Proc.Natl.Acad.Sci.USA / Year: 2000
Title: Diabetes-associated Mutations in a beta-Cell Transcription Factor Destabilize an Antiparallel "mini-zipper" in a Dimerization Interface
Authors: Hua, Q.X. / Zhao, M. / Narayana, N. / Nakagawa, S.H. / Jia, W. / Weiss, M.A.
#3: Journal: J.Mol.Biol. / Year: 1998
Title: The Relationship Between Insulin Bioactivity and Structure in the NH2-terminal A-chain Helix
Authors: Olsen, H.B. / Ludvigsen, S. / Kaarsholm, N.C.
#4: Journal: J.Mol.Biol. / Year: 1996
Title: Mapping the Functional Surface of Insulin by Design: Structure and Function of Novel A-chain Analogue
Authors: Hua, Q.X. / Hu, S.Q. / Frank, B.H. / Jia, W. / Chu, Y.C. / Wang, S.H. / Burke, G.T. / Katsoyannis, P.G. / Weiss, M.A.
History
DepositionJun 8, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2001Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Derived calculations / Version format compliance
Revision 1.3Oct 27, 2021Group: Advisory / Database references / Derived calculations
Category: database_2 / pdbx_database_remark ...database_2 / pdbx_database_remark / 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 / _pdbx_database_remark.text / _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.ptnr1_symmetry / _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_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 16, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.5Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature
Remark 400COMPOUND The crystallographic asymmetric unit of insulin consists of two insulin monomers each ...COMPOUND The crystallographic asymmetric unit of insulin consists of two insulin monomers each consisting of two heterochains. The entry presents coordinates for monomer 1 (chain indicators A and B) and monomer 2 (chain indicators C and D). There are two zinc ions per insulin hexamer located on the three-fold axis. The conformations of two monomers are different as the result of a change in conformation of the first eight residues of the B-chain.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: insulin a
B: insulin b
C: insulin a
D: insulin b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8226
Polymers11,6914
Non-polymers1312
Water64936
1
A: insulin a
B: insulin b
hetero molecules

A: insulin a
B: insulin b
hetero molecules

A: insulin a
B: insulin b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,7339
Polymers17,5376
Non-polymers1963
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 area5220 Å2
ΔGint-90 kcal/mol
Surface area10590 Å2
MethodPISA
2
C: insulin a
D: insulin b
hetero molecules

C: insulin a
D: insulin b
hetero molecules

C: insulin a
D: insulin b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,7339
Polymers17,5376
Non-polymers1963
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 area5190 Å2
ΔGint-117 kcal/mol
Surface area10870 Å2
MethodPISA
3
A: insulin a
B: insulin b
C: insulin a
D: insulin b
hetero molecules

A: insulin a
B: insulin b
C: insulin a
D: insulin b
hetero molecules

A: insulin a
B: insulin b
C: insulin a
D: insulin b
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,46718
Polymers35,07412
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 area17590 Å2
ΔGint-263 kcal/mol
Surface area14280 Å2
MethodPISA, PQS
Unit cell
Length a, b, c (Å)80.652, 80.652, 37.936
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-41-

ZN

21D-42-

ZN

DetailsThe biological assembly is a hexamer generated from the dimer in the asymmetric unit by the operations: -y, x-y, z and -x+y, -x, z.

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Components

#1: Protein/peptide insulin a


Mass: 2411.774 Da / Num. of mol.: 2 / Mutation: T8K / Source method: obtained synthetically
Details: This peptide was chemically synthesized. The sequence of the peptide is naturally found in Homo sapiens (humans).
References: UniProt: P01308
#2: Protein/peptide insulin b


Mass: 3433.953 Da / Num. of mol.: 2 / Source method: obtained synthetically
Details: This peptide was chemically synthesized. The sequence of the peptide is naturally found in Homo sapiens (humans).
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.: 36 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.03 Å3/Da / Density % sol: 39.43 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7
Details: Tris, sodium citrate, acetone, phenol, pH 7.0, VAPOR DIFFUSION, HANGING DROP
Temp details: ambient
Crystal grow
*PLUS
pH: 7.8
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
110 mg/mlprotein1drop
20.02 M1dropHCl
30.1 MTris-HCl1reservoir
40.1 Msodium citrate1reservoirpH7.8
50.02 %zinc acetate1reservoir
68 %acetate1reservoir
70.5 %phenol1reservoir

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Data collection

DiffractionMean temperature: 290 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jan 1, 2000 / Details: mirrors
RadiationMonochromator: MIRROR / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.5→10 Å / Num. all: 3369 / Num. obs: 3169 / % possible obs: 99.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 1 / Redundancy: 2 % / Rmerge(I) obs: 0.071
Reflection shellResolution: 2.5→2.59 Å / Rmerge(I) obs: 0.16 / % possible all: 97.5
Reflection
*PLUS
Rmerge(I) obs: 0.076

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
X-PLORmodel building
X-PLOR3.1refinement
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1TRZ

1trz


Resolution: 2.5→10 Å / σ(F): 2 / σ(I): 1
RfactorNum. reflection% reflectionSelection details
Rfree0.241 300 -RANDOM
Rwork0.204 ---
all-3213 --
obs-3160 89.2 %-
Refinement stepCycle: LAST / Resolution: 2.5→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms803 0 2 36 841
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg2.4
X-RAY DIFFRACTIONx_dihedral_angle_d23.8
X-RAY DIFFRACTIONx_improper_angle_d0.68
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.5 Å / Lowest resolution: 10 Å / σ(F): 2 / Rfactor obs: 0.204
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg23.8
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg0.68

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