Design of an allosterically modulated doxycycline and doxorubicin drug-binding protein

Proceedings of the National Academy of Sciences of the United States of America
Karin SchmidtYves A Muller

Abstract

The allosteric interplay between distant functional sites present in a single protein provides for one of the most important regulatory mechanisms in biological systems. While the design of ligand-binding sites into proteins remains challenging, this holds even truer for the coupling of a newly engineered binding site to an allosteric mechanism that regulates the ligand affinity. Here it is shown how computational design algorithms enabled the introduction of doxycycline- and doxorubicin-binding sites into the serine proteinase inhibitor (serpin) family member α1-antichymotrypsin. Further engineering allowed exploitation of the proteinase-triggered serpin-typical S-to-R transition to modulate the ligand affinities. These design variants follow strategies observed in naturally occurring plasma globulins that allow for the targeted delivery of hormones in the blood. By analogy, we propose that the variants described in the present study could be further developed to allow for the delivery of the antibiotic doxycycline and the anticancer compound doxorubicin to tissues/locations that express specific proteinases, such as bacterial infection sites or tumor cells secreting matrix metalloproteinases.

References

Aug 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·G L HammondC W Bardin
Apr 20, 1967·Biochemical and Biophysical Research Communications·I Schechter, A Berger
Mar 30, 2001·The Journal of Biological Chemistry·S J KridelJ W Smith
Dec 12, 2002·Chemical Reviews·Peter G W Gettins
Apr 1, 1963·Journal of Molecular Biology·J MONODF JACOB
Dec 4, 2003·Journal of the American Chemical Society·W Bruce Turnbull, Antonio H Daranas
Dec 31, 2003·Methods : a Companion to Methods in Enzymology·Timothy R DaffornStephen P Bottomley
Feb 3, 2005·Journal of the American Chemical Society·Frank V CochranWilliam F DeGrado
May 16, 2006·Acta Crystallographica. Section D, Biological Crystallography·Martin T Stiebritz, Yves A Muller
Aug 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Aiwu ZhouRobin W Carrell
Jul 24, 2007·The Journal of Biological Chemistry·Michael A KlieberYves A Muller
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Feb 18, 2011·The Journal of Biological Chemistry·Xiaoqiang QiAiwu Zhou
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Jun 5, 2012·Journal of the American Chemical Society·Katelyn DeckertJohn Karanicolas
Jan 28, 2014·Current Opinion in Chemical Biology·Kaspar Feldmeier, Birte Höcker
Feb 12, 2014·PLoS Computational Biology·Chung-Jung Tsai, Ruth Nussinov
Nov 27, 2014·PloS One·Wee Lee ChanRandy J Read
Dec 23, 2015·Nature Methods·Noah D TaylorSrivatsan Raman
Jul 16, 2016·Pharmacology & Therapeutics·David HenleyRobin Carrell

❮ Previous
Next ❯

Citations

Dec 4, 2019·Journal of Drug Targeting·Mehwish Saba Aslam, Liudi Yuan
Aug 31, 2018·Accounts of Chemical Research·Jan-Philipp GüntherPeer Fischer
Jul 25, 2019·Current Opinion in Chemical Biology·William M DawsonDerek N Woolfson

❮ 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.