5EMS

Crystal Structure of an iodinated insulin analog

Summary for 5EMS

• Entry DOI: 10.2210/pdb5ems/pdb
• Descriptor: Insulin, PHENOL, ZINC ION, ... (6 entities in total)
• Functional Keywords: insulin, hormone, non-standard modification, protein design, protein engineering
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 12
• Total formula weight: 36331.54

Authors

Lawrence, M.C.,Pandyarajan, V.,Wan, Z.,Weiss, M.A. (deposition date: 2015-11-06, release date: 2016-11-16, Last modification date: 2024-11-20)

Primary citation

El Hage, K.,Pandyarajan, V.,Phillips, N.B.,Smith, B.J.,Menting, J.G.,Whittaker, J.,Lawrence, M.C.,Meuwly, M.,Weiss, M.A.
Extending Halogen-based Medicinal Chemistry to Proteins: IODO-INSULIN AS A CASE STUDY.
J. Biol. Chem., 291:27023-27041, 2016

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) 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]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, Phe, Phe, 3-I-Tyr, 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]insulin analog (determined as an R zinc hexamer). Given that residues B24-B30 detach from the core on receptor binding, the environment of 3-I-Tyr 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 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.

PubMed: 27875310
DOI: 10.1074/jbc.M116.761015

Experimental method

X-RAY DIFFRACTION (2.3 Å)