An Interface-Driven Design Strategy Yields a Novel, Corrugated Protein Architecture

ACS Synthetic Biology
Mohammad ElGamacyAndrei Lupas

Abstract

Designing proteins with novel folds remains a major challenge, as the biophysical properties of the target fold are not known a priori and no sequence profile exists to describe its features. Therefore, most computational design efforts so far have been directed toward creating proteins that recapitulate existing folds. Here we present a strategy centered upon the design of novel intramolecular interfaces that enables the construction of a target fold from a set of starting fragments. This strategy effectively reduces the amount of computational sampling necessary to achieve an optimal sequence, without compromising the level of topological control. The solenoid architecture has been a target of extensive protein design efforts, as it provides a highly modular platform of low topological complexity. However, none of the previous efforts have attempted to depart from the natural form, which is characterized by a uniformly handed superhelical architecture. Here we aimed to design a more complex platform, abolishing the superhelicity by introducing internally alternating handedness, resulting in a novel, corrugated architecture. We employed our interface-driven strategy, designing three proteins and confirming the design by solvin...Continue Reading

References

Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Nov 28, 2000·Acta Crystallographica. Section D, Biological Crystallography·A Vagin, A Teplyakov
Sep 2, 2003·Current Opinion in Structural Biology·Ewan R G MainLynne Regan
Sep 21, 2004·Proceedings of the National Academy of Sciences of the United States of America·Cecilia C Mello, Doug Barrick
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·E Krissinel, K Henrick
Apr 26, 2005·Nucleic Acids Research·Yang Zhang, Jeffrey Skolnick
May 26, 2005·Protein Expression and Purification·F William Studier
Jul 21, 2005·Journal of the American Chemical Society·Tommi KajanderLynne Regan
Oct 14, 2005·Journal of Computational Chemistry·James C PhillipsKlaus Schulten
Feb 15, 2007·Proceedings of the National Academy of Sciences of the United States of America·Alan R Lowe, Laura S Itzhaki
Oct 30, 2007·Archives of Biochemistry and Biophysics·Ellen KlossDoug Barrick
Dec 15, 2007·Journal of Molecular Biology·Marie-Line GarronStefan T Arold
Jan 1, 2008·Journal of Molecular Biology·Svava K WetzelAndreas Plückthun
Jan 30, 2009·Protein Science : a Publication of the Protein Society·Will Sheffler, David Baker
Aug 4, 2009·Journal of Molecular Biology·David E KimDavid Baker
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Jul 27, 2010·Journal of Molecular Biology·Svava K WetzelOliver Zerbe
Oct 1, 1999·Journal of Biomolecular NMR·T DiercksH Kessler
Jan 8, 2011·Protein Science : a Publication of the Protein Society·Panagiotis L KastritisJoël Janin
Feb 21, 2013·Methods in Enzymology·Andrew Leaver-FayBrian Kuhlman
Dec 3, 2014·Journal of Molecular Biology·Fabio ParmeggianiDavid Baker
Dec 5, 2014·PLoS Computational Biology·Hua ChengNick V Grishin
Jan 7, 2015·Annual Review of Pharmacology and Toxicology·Andreas Plückthun
Jan 13, 2015·Nature Structural & Molecular Biology·Keunwan ParkDavid Baker
Jun 21, 2015·Current Opinion in Structural Biology·Derek N WoolfsonChristopher W Wood
Nov 1, 2015·Biochemical Society Transactions·Pamela J E RowlingLaura S Itzhaki
May 1, 2016·Nucleic Acids Research·Liisa Holm, Laura M Laakso
Sep 16, 2016·Nature·Po-Ssu HuangDavid Baker
Mar 8, 2017·Current Opinion in Structural Biology·Fabio Parmeggiani, Po-Ssu Huang
Sep 13, 2017·Scientific Reports·Yufan WuAndreas Plückthun

❮ Previous
Next ❯

Citations

Feb 12, 2020·Quarterly Reviews of Biophysics·Ivan V Korendovych, William F DeGrado
Aug 4, 2019·Protein Engineering, Design & Selection : PEDS·Megan C CohanRohit V Pappu
Dec 23, 2020·PLoS Biology·Birte Hernandez AlvarezMohammad ElGamacy
Jan 10, 2020·Current Opinion in Structural Biology·Peer Re MittlAndreas Plückthun
Mar 16, 2021·Current Opinion in Structural Biology·Frances Gidley, Fabio Parmeggiani
May 9, 2021·Current Opinion in Structural Biology·Mohammad ElGamacy, Birte Hernandez Alvarez
Jul 24, 2021·Journal of Molecular Biology·Derek N Woolfson
Jul 16, 2021·Nature·John JumperDemis Hassabis

❮ 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.