5EMS

Crystal Structure of an iodinated insulin analog

  • Classification: HORMONE
  • Organism(s): Homo sapiens
  • Mutation(s): Yes 

  • Deposited: 2015-11-06 Released: 2016-11-16 
  • Deposition Author(s): Lawrence, M.C., Pandyarajan, V., Wan, Z., Weiss, M.A.
  • Funding Organization(s): National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS), National Health and Medical Research Council (NHMRC, Australia)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.170 

wwPDB Validation   3D Report Full Report


This is version 1.7 of the entry. See complete history


Literature

Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.

El Hage, K.Pandyarajan, V.Phillips, N.B.Smith, B.J.Menting, J.G.Whittaker, J.Lawrence, M.C.Meuwly, M.Weiss, M.A.

(2016) J Biol Chem 291: 27023-27041

  • DOI: https://doi.org/10.1074/jbc.M116.761015
  • Primary Citation of Related Structures:  
    5EMS

  • PubMed Abstract: 

    Insulin, a protein critical for metabolic homeostasis, provides a classical model for protein design with application to human health. Recent efforts to improve its pharmaceutical formulation demonstrated that iodination of a conserved tyrosine (Tyr B26 ) enhances key properties of a rapid-acting clinical analog. Moreover, the broad utility of halogens in medicinal chemistry has motivated the use of hybrid quantum- and molecular-mechanical methods to study proteins. Here, we (i) undertook quantitative atomistic simulations of 3-[iodo-Tyr B26 ]insulin to predict its structural features, and (ii) tested these predictions by X-ray crystallography. Using an electrostatic model of the modified aromatic ring based on quantum chemistry, the calculations suggested that the analog, as a dimer and hexamer, exhibits subtle differences in aromatic-aromatic interactions at the dimer interface. Aromatic rings (Tyr B16 , Phe B24 , Phe B25 , 3-I-Tyr B26 , and their symmetry-related mates) at this interface adjust to enable packing of the hydrophobic iodine atoms within the core of each monomer. Strikingly, these features were observed in the crystal structure of a 3-[iodo-Tyr B26 ]insulin analog (determined as an R 6 zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr B26 in a receptor complex must differ from that in the free hormone. Based on the recent structure of a "micro-receptor" complex, we predict that 3-I-Tyr B26 engages the receptor via directional halogen bonding and halogen-directed hydrogen bonding as follows: favorable electrostatic interactions exploiting, respectively, the halogen's electron-deficient σ-hole and electronegative equatorial band. Inspired by quantum chemistry and molecular dynamics, such "halogen engineering" promises to extend principles of medicinal chemistry to proteins.


  • Organizational Affiliation

    From the Department of Chemistry, University of Basel, Klingelbergstrasse 80 CH-4056 Basel, Switzerland.


Macromolecules

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin
A, C, E, G, I
A, C, E, G, I, K
21Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P01308 (Homo sapiens)
Explore P01308 
Go to UniProtKB:  P01308
PHAROS:  P01308
GTEx:  ENSG00000254647 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01308
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Insulin
B, D, F, H, J
B, D, F, H, J, L
30Homo sapiensMutation(s): 1 
UniProt & NIH Common Fund Data Resources
Find proteins for P01308 (Homo sapiens)
Explore P01308 
Go to UniProtKB:  P01308
PHAROS:  P01308
GTEx:  ENSG00000254647 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01308
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IPH
Query on IPH

Download Ideal Coordinates CCD File 
M [auth A]
O [auth C]
R [auth E]
T [auth G]
U [auth I]
M [auth A],
O [auth C],
R [auth E],
T [auth G],
U [auth I],
V [auth K]
PHENOL
C6 H6 O
ISWSIDIOOBJBQZ-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
N [auth B],
P [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
Q [auth D],
S [auth F]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
IYR
Query on IYR
B, D, F, H, J
B, D, F, H, J, L
L-PEPTIDE LINKINGC9 H10 I N O3TYR
NLE
Query on NLE
B, D, F, H, J
B, D, F, H, J, L
L-PEPTIDE LINKINGC6 H13 N O2LEU
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.170 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 46.43α = 90
b = 61.63β = 111.38
c = 58.58γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesR01 DK04949
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesDK079233
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)United StatesF30 DK094685-04
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesT32 GM007250
National Health and Medical Research Council (NHMRC, Australia)Australia1005896
National Health and Medical Research Council (NHMRC, Australia)Australia1058233
National Health and Medical Research Council (NHMRC, Australia)Australia361646

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-16
    Type: Initial release
  • Version 1.1: 2016-11-23
    Changes: Database references
  • Version 1.2: 2016-12-21
    Changes: Database references
  • Version 1.3: 2017-01-11
    Changes: Database references
  • Version 1.4: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.5: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.6: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.7: 2023-11-15
    Changes: Data collection