Solvent-accessibility of discrete residue positions in the polypeptide hormone glucagon by (19)F-NMR observation of 4-fluorophenylalanine

Journal of Biomolecular NMR
Yaguang HouKurt Wüthrich

Abstract

The amino acid 4-fluoro-L-phenylalanine (4F-Phe) was introduced at the positions of Phe6 and Phe22 in the 29-residue polypeptide hormone glucagon by expressing glucagon in E. coli in the presence of an excess of 4F-Phe. Glucagon regulates blood glucose homeostasis by interaction with the glucagon receptor (GCGR), a class B GPCR. By referencing to the 4F-Phe chemical shifts at varying D2O concentrations, the solvent exposure of the two Phe sites along the glucagon sequence was determined, showing that 4F-Phe6 was fully solvent exposed and 4F-Phe22 was only partially exposed. The incorporation of fluorine atoms in polypeptide hormones paves the way for novel studies of their interactions with membrane-spanning receptors, specifically by differentiating between effects on the solvent accessibility, the line shapes, and the chemical shifts from interactions with lipids, detergents and proteins. Studies of interactions of GCGR with ligands in solution is at this point of keen interest, given that recent crystallographic studies revealed that an apparent small molecule antagonist actually binds as an allosteric effector at a distance of ~20 Å from the orthosteric ligand binding site (Jazayeri et al., in Nature 533:274-277, 2016).

References

Mar 1, 1984·Journal of Medicinal Chemistry·J Sueiras-DiazD H Coy
Aug 1, 1995·Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Métabolisme·A PereaI Valverde
Nov 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·J Klein-SeetharamanH G Khorana
Mar 5, 2003·Pharmacological Reviews·Kelly E MayoDaniel J Drucker
Mar 11, 2003·American Journal of Physiology. Endocrinology and Metabolism·Guoqiang Jiang, Bei B Zhang
Oct 27, 2004·Biochemistry·James G Bann, Carl Frieden
Aug 6, 2009·Journal of Biomolecular NMR·Julianne L Kitevski-LeBlancR Scott Prosser
Dec 7, 2010·Journal of Diabetes Science and Technology·Joseph R ChabenneRichard D DiMarchi
Oct 4, 2011·Biochemical and Biophysical Research Communications·Pan ShiChanglin Tian
Mar 1, 2012·Progress in Nuclear Magnetic Resonance Spectroscopy·Julianne L Kitevski-LeBlanc, R Scott Prosser
May 17, 2012·Current Diabetes Reviews·Robert L Rodgers
Jun 1, 2013·Journal of the American Chemical Society·Tae Hun KimR Scott Prosser
Jul 19, 2013·Nature·Fai Yiu SiuRaymond C Stevens
Jul 19, 2013·Chemical Society Reviews·Han ChenLing Peng
Aug 13, 2013·Current Opinion in Structural Biology·Tatiana DidenkoKurt Wüthrich
Dec 24, 2013·Trends in Pharmacological Sciences·Kaspar HollensteinRaymond C Stevens
Feb 18, 2014·International Journal of Molecular Sciences·Lenea Nørskov-LauritsenHans Bräuner-Osborne
Apr 26, 2014·ACS Chemical Biology·E Neil G Marsh, Yuta Suzuki
Aug 15, 2014·Diabetes Research and Clinical Practice·Dominique Bataille, Stéphane Dalle
Jun 20, 2015·Cell·Jill E ChrencikMichael A Hanson
Apr 26, 2016·Nature·Ali JazayeriFiona H Marshall

❮ Previous
Next ❯

Citations

Nov 10, 2018·Nature Reviews. Drug Discovery·Ichio ShimadaKurt Wüthrich

❮ Previous
Next ❯

Methods Mentioned

BETA
NMR

Software Mentioned

zgfhigqn30

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.

Related Papers

Advances in Experimental Medicine and Biology
Nuska Tschammer
Protein Science : a Publication of the Protein Society
H Kenney Basehore, Ira J Ropson
© 2022 Meta ULC. All rights reserved