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Degrado protein

Haifan Wu, Arusha Acharyya, Yibing Wu, Lijun Liu, Hyunil Jo, Feng Gai, William DeGrado
Although helices play key roles in peptide-protein and protein-protein interactions, the helical conformation is generally unstable for short peptides (10 - 15 residues) in aqueous solution in the absence of their binding partners. Thus, stabilizing the helical conformation of peptides can lead to increases in binding potency, specificity, and stability towards proteolytic degradation. Helices have been successfully stabilized by introducing sidechain-to-sidechain cross-links within the central portion of the helix...
February 7, 2018: Chembiochem: a European Journal of Chemical Biology
Shao-Qing Zhang, Marco Chino, Lijun Liu, Youzhi Tang, Xiaozhen Hu, William F DeGrado, Angela Lombardi
De novo design provides an attractive approach to test the mechanism by which metalloproteins define the geometry and reactivity of their metal ion cofactors. While there has been considerable progress in designing proteins that bind transition metal ions including iron-sulfur clusters, the design of tetranuclear clusters with oxygen-rich environments has not been accomplished. Here, we describe the design of tetranuclear clusters, consisting of four Zn2+ and four carboxylate oxygens situated at the vertices of a distorted cube-like structure...
January 31, 2018: Journal of the American Chemical Society
Nicholas F Polizzi, Yibing Wu, Thomas Lemmin, Alison M Maxwell, Shao-Qing Zhang, Jeff Rawson, David N Beratan, Michael J Therien, William F DeGrado
Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 °C. The high-resolution structure of holo-PS1 is in sub-Å agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry...
December 2017: Nature Chemistry
Bobo Dang, Haifan Wu, Vikram Khipple Mulligan, Marco Mravic, Yibing Wu, Thomas Lemmin, Alexander Ford, Daniel-Adriano Silva, David Baker, William F DeGrado
The folding of natural proteins typically relies on hydrophobic packing, metal binding, or disulfide bond formation in the protein core. Alternatively, a 3D structure can be defined by incorporating a multivalent cross-linking agent, and this approach has been successfully developed for the selection of bicyclic peptides from large random-sequence libraries. By contrast, there is no general method for the de novo computational design of multicross-linked proteins with predictable and well-defined folds, including ones not found in nature...
October 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
Nathan H Joh, Gevorg Grigoryan, Yibing Wu, William F DeGrado
Ion transporters and channels are able to identify and act on specific substrates among myriads of ions and molecules critical to cellular processes, such as homeostasis, cell signalling, nutrient influx and drug efflux. Recently, we designed Rocker, a minimalist model for Zn(2+)/H(+) co-transport. The success of this effort suggests that de novo membrane protein design has now come of age so as to serve a key approach towards probing the determinants of membrane protein folding, assembly and function. Here, we review general principles that can be used to design membrane proteins, with particular reference to helical assemblies with transport function...
August 5, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Myungwoon Lee, Tuo Wang, Olga V Makhlynets, Yibing Wu, Nicholas F Polizzi, Haifan Wu, Pallavi M Gosavi, Jan Stöhr, Ivan V Korendovych, William F DeGrado, Mei Hong
Throughout biology, amyloids are key structures in both functional proteins and the end product of pathologic protein misfolding. Amyloids might also represent an early precursor in the evolution of life because of their small molecular size and their ability to self-purify and catalyze chemical reactions. They also provide attractive backbones for advanced materials. When β-strands of an amyloid are arranged parallel and in register, side chains from the same position of each chain align, facilitating metal chelation when the residues are good ligands such as histidine...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
Mary Rose Hilaire, Ismail A Ahmed, Chun-Wei Lin, Hyunil Jo, William F DeGrado, Feng Gai
Many fluorescent proteins are currently available for biological spectroscopy and imaging measurements, allowing a wide range of biochemical and biophysical processes and interactions to be studied at various length scales. However, in applications where a small fluorescence reporter is required or desirable, the choice of fluorophores is rather limited. As such, continued effort has been devoted to the development of amino acid-based fluorophores that do not require a specific environment and additional time to mature and have a large fluorescence quantum yield, long fluorescence lifetime, good photostability, and an emission spectrum in the visible region...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
Tuo Wang, Hyunil Jo, William F DeGrado, Mei Hong
Water is essential for protein folding and assembly of amyloid fibrils. Internal water cavities have been proposed for several amyloid fibrils, but no direct structural and dynamical data have been reported on the water dynamics and site-specific interactions of water with the fibrils. Here we use solid-state NMR spectroscopy to investigate the water interactions of several Aβ40 fibrils. (1)H spectral lineshapes, T2 relaxation times, and two-dimensional (2D) (1)H-(13)C correlation spectra show that there are five distinct water pools: three are peptide-bound water, while two are highly dynamic water that can be assigned to interfibrillar water and bulk-like matrix water...
April 21, 2017: Journal of the American Chemical Society
Steven Seaman, Zhongyu Zhu, Saurabh Saha, Xiaoyan M Zhang, Mi Young Yang, Mary Beth Hilton, Karen Morris, Christopher Szot, Holly Morris, Deborah A Swing, Lino Tessarollo, Sean W Smith, Sylvia Degrado, Dmitry Borkin, Nareshkumar Jain, Julia Scheiermann, Yang Feng, Yanping Wang, Jinyu Li, Dean Welsch, Gary DeCrescenzo, Amit Chaudhary, Enrique Zudaire, Kimberly D Klarmann, Jonathan R Keller, Dimiter S Dimitrov, Brad St Croix
Targeting the tumor vasculature with antibody-drug conjugates (ADCs) is a promising anti-cancer strategy that in order to be realized must overcome several obstacles, including identification of suitable targets and optimal warheads. Here, we demonstrate that the cell-surface protein CD276/B7-H3 is broadly overexpressed by multiple tumor types on both cancer cells and tumor-infiltrating blood vessels, making it a potentially ideal dual-compartment therapeutic target. In preclinical studies CD276 ADCs armed with a conventional MMAE warhead destroyed CD276-positive cancer cells, but were ineffective against tumor vasculature...
April 10, 2017: Cancer Cell
Felix Findeisen, Marta Campiglio, Hyunil Jo, Fayal Abderemane-Ali, Christine H Rumpf, Lianne Pope, Nathan D Rossen, Bernhard E Flucher, William F DeGrado, Daniel L Minor
For many voltage-gated ion channels (VGICs), creation of a properly functioning ion channel requires the formation of specific protein-protein interactions between the transmembrane pore-forming subunits and cystoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta-xylyl (m-xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore-forming subunit α-interaction domain (AID) and cytoplasmic β-subunit (CaVβ)...
June 21, 2017: ACS Chemical Neuroscience
Nathan W Schmidt, Gevorg Grigoryan, William F DeGrado
Coiled-coils are essential components of many protein complexes. First discovered in structural proteins such as keratins, they have since been found to figure largely in the assembly and dynamics required for diverse functions, including membrane fusion, signal transduction and motors. Coiled-coils have a characteristic repeating seven-residue geometric and sequence motif, which is sometimes interrupted by the insertion of one or more residues. Such insertions are often highly conserved and critical to interdomain communication in signaling proteins such as bacterial histidine kinases...
March 2017: Protein Science: a Publication of the Protein Society
Matthew R Elkins, Tuo Wang, Mimi Nick, Hyunil Jo, Thomas Lemmin, Stanley B Prusiner, William F DeGrado, Jan Stöhr, Mei Hong
The amyloid-β (Aβ) peptide of Alzheimer's disease (AD) forms polymorphic fibrils on the micrometer and molecular scales. Various fibril growth conditions have been identified to cause polymorphism, but the intrinsic amino acid sequence basis for this polymorphism has been unclear. Several single-site mutations in the center of the Aβ sequence cause different disease phenotypes and fibrillization properties. The E22G (Arctic) mutant is found in familial AD and forms protofibrils more rapidly than wild-type Aβ...
August 10, 2016: Journal of the American Chemical Society
Tsz-Leung To, Katalin F Medzihradszky, Alma L Burlingame, William F DeGrado, Hyunil Jo, Xiaokun Shu
Protein-protein interactions regulate many biological processes. Identification of interacting proteins is thus an important step toward molecular understanding of cell signaling. The aim of this study was to investigate the use of photo-generated singlet oxygen and a small molecule for proximity labeling of interacting proteins in cellular environment. The protein of interest (POI) was fused with a small singlet oxygen photosensitizer (miniSOG), which generates singlet oxygen ((1)O2) upon irradiation. The locally generated singlet oxygen then activated a biotin-conjugated thiol molecule to form a covalent bond with the proteins nearby...
July 15, 2016: Bioorganic & Medicinal Chemistry Letters
Kook-Han Kim, Dong-Kyun Ko, Yong-Tae Kim, Nam Hyeong Kim, Jaydeep Paul, Shao-Qing Zhang, Christopher B Murray, Rudresh Acharya, William F DeGrado, Yong Ho Kim, Gevorg Grigoryan
Learning to engineer self-assembly would enable the precise organization of molecules by design to create matter with tailored properties. Here we demonstrate that proteins can direct the self-assembly of buckminsterfullerene (C60) into ordered superstructures. A previously engineered tetrameric helical bundle binds C60 in solution, rendering it water soluble. Two tetramers associate with one C60, promoting further organization revealed in a 1.67-Å crystal structure. Fullerene groups occupy periodic lattice sites, sandwiched between two Tyr residues from adjacent tetramers...
2016: Nature Communications
Jessica L Thomaston, William F DeGrado
The M2 protein is a small proton channel found in the influenza A virus that is necessary for viral replication. The M2 channel is the target of a class of drugs called the adamantanes, which block the channel pore and prevent the virus from replicating. In recent decades mutations have arisen in M2 that prevent the adamantanes from binding to the channel pore, with the most prevalent of these mutations being S31N. Here we report the first crystal structure of the S31N mutant crystallized using lipidic cubic phase crystallization techniques and solved to 1...
August 2016: Protein Science: a Publication of the Protein Society
Gözde Ulas, Thomas Lemmin, Yibing Wu, George T Gassner, William F DeGrado
Enzymes use binding energy to stabilize their substrates in high-energy states that are otherwise inaccessible at ambient temperature. Here we show that a de novo designed Zn(II) metalloprotein stabilizes a chemically reactive organic radical that is otherwise unstable in aqueous media. The protein binds tightly to and stabilizes the radical semiquinone form of 3,5-di-tert-butylcatechol. Solution NMR spectroscopy in conjunction with molecular dynamics simulations show that the substrate binds in the active site pocket where it is stabilized by metal-ligand interactions as well as by burial of its hydrophobic groups...
April 2016: Nature Chemistry
Mukesh K Pandey, Timothy R DeGrado
Glycogen synthase kinase-3 (GSK-3) is associated with various key biological processes, including glucose regulation, apoptosis, protein synthesis, cell signaling, cellular transport, gene transcription, proliferation, and intracellular communication. Accordingly, GSK-3 has been implicated in a wide variety of diseases and specifically targeted for both therapeutic and imaging applications by a large number of academic laboratories and pharmaceutical companies. Here, we review the structure, function, expression levels, and ligand-binding properties of GSK-3 and its connection to various diseases...
2016: Theranostics
Binxia Yang, Akshaar Brahmbhatt, Evelyn Nieves Torres, Brian Thielen, Deborah L McCall, Sean Engel, Aditya Bansal, Mukesh K Pandey, Allan B Dietz, Edward B Leof, Timothy R DeGrado, Debabrata Mukhopadhyay, Sanjay Misra
PURPOSE: To determine if adventitial transplantation of human adipose tissue-derived mesenchymal stem cells (MSCs) to the outflow vein of B6.Cg-Foxn1(nu)/J mice with arteriovenous fistula (AVF) at the time of creation would reduce monocyte chemoattractant protein-1 (Mcp-1) gene expression and venous neointimal hyperplasia. The second aim was to track transplanted zirconium 89 ((89)Zr)-labeled MSCs serially with positron emission tomography (PET) for 21 days. MATERIALS AND METHODS: All animal experiments were performed according to protocols approved by the institutional animal care and use committee...
May 2016: Radiology
Rae Ana Snyder, Justine Betzu, Susan E Butch, Amanda J Reig, William F DeGrado, Edward I Solomon
DFsc (single-chain due ferri) proteins allow for modeling binuclear non-heme iron enzymes with a similar fold. Three 4A → 4G variants of DFsc were studied to investigate the effects of (1) increasing the size of the substrate/solvent access channel (G4DFsc), (2) including an additional His residue in the first coordination sphere along with three additional helix-stabilizing mutations [3His-G4DFsc(Mut3)], and (3) the three helix-stabilizing mutations alone [G4DFsc(Mut3)] on the biferrous structures and their O2 reactivities...
August 4, 2015: Biochemistry
Rae Ana Snyder, Susan E Butch, Amanda J Reig, William F DeGrado, Edward I Solomon
Using the single-chain due ferri (DFsc) peptide scaffold, the differential oxidase and oxygenase reactivities of two 4A→4G variants, one with two histidines at the diiron center (G4DFsc) and the other with three histidines (3His-G4DFsc(Mut3)), are explored. By controlling the reaction conditions, the active form responsible for 4-aminophenol (4-AP) oxidase activity in both G4DFsc and 3His-G4DFsc(Mut3) is determined to be the substrate-bound biferrous site. Using circular dichroism (CD), magnetic CD (MCD), and variable-temperature, variable-field (VTVH) MCD spectroscopies, 4-AP is found to bind directly to the biferrous sites of the DF proteins...
July 29, 2015: Journal of the American Chemical Society
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