Refinement of a homology model of the mu-opioid receptor using distance constraints from intrinsic and engineered zinc-binding sites

Biochemistry
Carol B FowlerHenry I Mosberg

Abstract

Publication of the rhodopsin X-ray structure has facilitated the development of homology models of other G protein-coupled receptors. However, possible shifts of transmembrane (TM) alpha helices, expected variations in helical distortions, and differences in loop size necessitate experimental verification of these comparative models. To refine a rhodopsin-based homology model of the mu-opioid receptor (MOR), we experimentally determined structural-distance constraints from intrinsic and engineered metal-binding sites in the rat MOR. Investigating the relatively high intrinsic affinity of MOR for Zn(2+) (IC(50) approximately 30microM), we observed that mutation of His(319) (TM7) abolished Zn(2+) inhibition of ligand binding, while mutation of Asp(216) (extracellular loop 2) decreased the effect of Zn(2+), suggesting these residues participate in the intrinsic Zn(2+)-binding center of MOR. To verify the relative orientation of TM5 and TM6 and to examine whether a rhodopsin-like alpha aneurism is present in TM5, we engineered Zn(2+)-binding centers by mutating residues of TM5 and TM6 to Cys or His, making use of the native His(297) in TM6 as an additional Zn(2+)-coordination site. Inhibition of opioid ligand binding by Zn(2+) sugg...Continue Reading

References

Apr 5, 1996·The Journal of Biological Chemistry·K ThirstrupT W Schwartz
May 29, 1999·Critical Reviews in Neurobiology·T S Shippenberg, G I Elmer
Nov 5, 1999·Biochimica Et Biophysica Acta·D R Flower
Feb 12, 2000·Journal of Medicinal Chemistry·G SubramanianD M Ferguson
Oct 6, 2001·Science·D Baker, A Sali
Sep 24, 2002·The Journal of Biological Chemistry·Birgitte HolstThue W Schwartz
Oct 18, 2002·Journal of Medicinal Chemistry·Manuela IadanzaHans-Dieter Höltje
Nov 1, 2002·The Journal of Biological Chemistry·Gayathri SwaminathBrian Kobilka
Dec 5, 2002·The Journal of Peptide Research : Official Journal of the American Peptide Society·H I Mosberg, C B Fowler
Jul 10, 2003·Annals of the New York Academy of Sciences·Birgitte Holst, Thue W Schwartz

❮ Previous
Next ❯

Citations

May 26, 2010·Journal of Molecular Modeling·Jianxin ChengYun Tang
Nov 15, 2006·Journal of Computer-aided Molecular Design·Masha Y NivHarel Weinstein
Jul 29, 2009·Applied Biochemistry and Biotechnology·Isabelle MullerFranck Jean Talmont
Aug 24, 2005·Biochemistry·Irina D PogozhevaHenry I Mosberg
Oct 1, 2009·Journal of Medicinal Chemistry·Lauren C PuringtonHenry I Mosberg
May 23, 2009·Nature Reviews. Drug Discovery·Mayako MichinoRaymond C Stevens
Feb 17, 2007·The Journal of Biological Chemistry·Paul S-H ParkDaniel J Muller
Aug 29, 2013·Biochemistry. Biokhimii︠a︡·S A Shukolyukov
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
Dec 16, 2005·The AAPS Journal·Irina D PogozhevaHenry I Mosberg
May 1, 2009·Future Medicinal Chemistry·Kimberly M LovellThomas E Prisinzano
Jul 1, 2008·FEBS Letters·Laura StorjohannThue W Schwartz
Oct 1, 2006·Expert Opinion on Drug Discovery·Adriano Martinelli, Tiziano Tuccinardi
Dec 23, 2008·General and Comparative Endocrinology·Andrea BaronRobert M Dores
Oct 28, 2008·Neuropharmacology·Sergio Barrondo, Joan Sallés
Aug 14, 2012·Chemical Biology & Drug Design·Jessica P AnandHenry I Mosberg
Dec 8, 2005·Biochemical and Biophysical Research Communications·Yong LiuKim A Neve
Aug 5, 2015·Substance Abuse Treatment, Prevention, and Policy·Diana CiubotariuCătălina Elena Lupușoru
Apr 5, 2005·Biophysical Journal·Antoine TalyJean-Pierre Changeux
Oct 22, 2008·Molecular Phylogenetics and Evolution·M Javier Herrero-Turrion, Raquel E Rodríguez
Apr 2, 2017·Journal of Computer-aided Molecular Design·A F Marmolejo-Valencia, K Martínez-Mayorga
Mar 29, 2006·The Journal of Biological Chemistry·Christian E EllingThue W Schwartz
Feb 24, 2017·Frontiers in Endocrinology·Chiraz GhaddhabJohnny Deladoëy
Jul 17, 2018·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Michael NelsonEdward J Catapane
Sep 15, 2005·Chemical Reviews·Francesca Fanelli, Pier G De Benedetti

❮ Previous
Next ❯

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.