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https://www.readbyqxmd.com/read/28483635/crystal-structure-of-tissue-factor-in-complex-with-antibody-10h10-reveals-the-signaling-epitope
#1
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Bingyuan Wu, Yonghong Zhao, Susann Taudte, G Mark Anderson, Gary L Gilliland
Tissue factor (TF) initiates the extrinsic pathway of blood coagulation through sequential binding and activation of coagulation factors VII (FVII) and X (FX). In addition, through activation of G-protein-coupled protease activated receptors (PARs) TF induces cell signaling that is related to cancer, angiogenesis and inflammation. Monoclonal antibodies (mAbs) proved to be a useful tool for studying the interplay between TF signaling and coagulation. MAb 10H10 is unique in that it blocks the signaling pathway and thus inhibits angiogenesis and tumor growth without interfering with coagulation...
May 5, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28471362/crystal-structure-of-cd27-in-complex-with-a-neutralizing-noncompeting-antibody
#2
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Gary L Gilliland
CD27 is a T-cell and B-cell co-stimulatory glycoprotein of the tumor necrosis factor (TNF) receptor superfamily that is dependent on the availability of the TNF-like ligand CD70. Therapeutic approaches to treating autoimmune diseases and cancers with antagonistic and agonistic anti-CD27 monoclonal antibodies (mAbs), respectively, have recently been developed. Mouse anti-human CD27 mAb 2177 shows potency in neutralizing CD70-induced signaling; however, it does not block the binding of soluble CD70. To provide insight into the mechanism of action of the mAb, the crystal structure of the CD27 extracellular domain in complex with the Fab fragment of mAb 2177 was determined at 1...
May 1, 2017: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/28424250/unifying-mechanism-for-different-fibrotic-diseases
#3
Gerlinde Wernig, Shih-Yu Chen, Lu Cui, Camille Van Neste, Jonathan M Tsai, Neeraja Kambham, Hannes Vogel, Yaso Natkunam, D Gary Gilliland, Garry Nolan, Irving L Weissman
Fibrotic diseases are not well-understood. They represent a number of different diseases that are characterized by the development of severe organ fibrosis without any obvious cause, such as the devastating diseases idiopathic pulmonary fibrosis (IPF) and scleroderma. These diseases have a poor prognosis comparable with endstage cancer and are uncurable. Given the phenotypic differences, it was assumed that the different fibrotic diseases also have different pathomechanisms. Here, we demonstrate that many endstage fibrotic diseases, including IPF; scleroderma; myelofibrosis; kidney-, pancreas-, and heart-fibrosis; and nonalcoholic steatohepatosis converge in the activation of the AP1 transcription factor c-JUN in the pathologic fibroblasts...
May 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28119207/epitope-dependent-mechanisms-of-cd27-neutralization-revealed-by-x-ray-crystallography
#4
Galina Obmolova, Alexey Teplyakov, Thomas J Malia, Nicole Wunderler, Deborah Kwok, Linda Barone, Raymond Sweet, Tatiana Ort, Michael Scully, Gary L Gilliland
CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different. The pharmacokinetics profiles could be epitope dependent...
March 2017: Molecular Immunology
https://www.readbyqxmd.com/read/27881684/conformational-flexibility-of-an-anti-il-13-darpin%C3%A2
#5
Alexey Teplyakov, Thomas J Malia, Galina Obmolova, Steven A Jacobs, Karyn T O'Neil, Gary L Gilliland
Designed ankyrin repeat proteins (DARPin(®)) are artificial non-immunoglobulin binding proteins with potential applications as therapeutic molecules. DARPin 6G9 binds interleukin-13 with high affinity and blocks the signaling pathway and as such is promising for the treatment of asthma and other atopic diseases. The crystal structures of DARPin 6G9 in the unbound form and in complex with IL-13 were determined at high resolution. The DARPin competes for the same epitope as the IL-13 receptor chain 13Rα1 but does not interfere with the binding of the other receptor chain, IL-4Rα...
January 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27737926/engineering-a-targeted-delivery-platform-using-centyrins
#6
Shalom D Goldberg, Rosa M F Cardoso, Tricia Lin, Tracy Spinka-Doms, Donna Klein, Steven A Jacobs, Vadim Dudkin, Gary Gilliland, Karyn T O'Neil
Targeted delivery of therapeutic payloads to specific tissues and cell types is an important component of modern pharmaceutical development. Antibodies or other scaffold proteins can provide the cellular address for delivering a covalently linked therapeutic via specific binding to cell-surface receptors. Optimization of the conjugation site on the targeting protein, linker chemistry and intracellular trafficking pathways can all influence the efficiency of delivery and potency of the drug candidate. In this study, we describe a comprehensive engineering experiment for an EGFR binding Centyrin, a highly stable fibronectin type III (FN3) domain, wherein all possible single-cysteine replacements were evaluated for expression, purification, conjugation efficiency, retention of target binding, biophysical properties and delivery of a cytotoxic small molecule payload...
December 2016: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/27525816/engineering-antibody-therapeutics
#7
REVIEW
Mark L Chiu, Gary L Gilliland
The successful introduction of antibody-based protein therapeutics into the arsenal of treatments for patients has within a few decades fostered intense innovation in the production and engineering of antibodies. Reviewed here are the methods currently used to produce antibodies along with how our knowledge of the structural and functional characterization of immunoglobulins has resulted in the engineering of antibodies to produce protein therapeutics with unique properties, both biological and biophysical, that are leading to novel therapeutic approaches...
June 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27461835/development-of-a-high-throughput-gene-expression-screen-for-modulators-of-ras-mapk-signaling-in-a-mutant-ras-cellular-context
#8
Bryan Severyn, Thi Nguyen, Michael D Altman, Lixia Li, Kumiko Nagashima, George N Naumov, Sriram Sathyanarayanan, Erica Cook, Erick Morris, Marc Ferrer, Bill Arthur, Yair Benita, Jim Watters, Andrey Loboda, Jeff Hermes, D Gary Gilliland, Michelle A Cleary, Pamela M Carroll, Peter Strack, Matt Tudor, Jannik N Andersen
The RAS-MAPK pathway controls many cellular programs, including cell proliferation, differentiation, and apoptosis. In colorectal cancers, recurrent mutations in this pathway often lead to increased cell signaling that may contribute to the development of neoplasms, thereby making this pathway attractive for therapeutic intervention. To this end, we developed a 26-member gene signature of RAS-MAPK pathway activity utilizing the Affymetrix QuantiGene Plex 2.0 reagent system and performed both primary and confirmatory gene expression-based high-throughput screens (GE-HTSs) using KRAS mutant colon cancer cells (SW837) and leveraging a highly annotated chemical library...
October 2016: Journal of Biomolecular Screening
https://www.readbyqxmd.com/read/27210805/structural-diversity-in-a-human-antibody-germline-library
#9
Alexey Teplyakov, Galina Obmolova, Thomas J Malia, Jinquan Luo, Salman Muzammil, Raymond Sweet, Juan Carlos Almagro, Gary L Gilliland
To support antibody therapeutic development, the crystal structures of a set of 16 germline variants composed of 4 different kappa light chains paired with 4 different heavy chains have been determined. All four heavy chains of the antigen-binding fragments (Fabs) have the same complementarity-determining region (CDR) H3 that was reported in an earlier Fab structure. The structure analyses include comparisons of the overall structures, canonical structures of the CDRs and the VH:VL packing interactions. The CDR conformations for the most part are tightly clustered, especially for the ones with shorter lengths...
August 2016: MAbs
https://www.readbyqxmd.com/read/26800003/epitope-mapping-and-structural-basis-for-the-recognition-of-phosphorylated-tau-by-the-anti-tau-antibody-at8
#10
Thomas J Malia, Alexey Teplyakov, Robin Ernst, Sheng-Jiun Wu, Eilyn R Lacy, Xuesong Liu, Marc Vandermeeren, Marc Mercken, Jinquan Luo, Raymond W Sweet, Gary L Gilliland
Microtubule-associated protein tau becomes abnormally phosphorylated in Alzheimer's disease and other tauopathies and forms aggregates of paired helical filaments (PHF-tau). AT8 is a PHF-tau-specific monoclonal antibody that is a commonly used marker of neuropathology because of its recognition of abnormally phosphorylated tau. Previous reports described the AT8 epitope to include pS202/pT205. Our studies support and extend previous findings by also identifying pS208 as part of the binding epitope. We characterized the phosphoepitope of AT8 through both peptide binding studies and costructures with phosphopeptides...
April 2016: Proteins
https://www.readbyqxmd.com/read/26165925/runx1-deficiency-decreases-ribosome-biogenesis-and-confers-stress-resistance-to-hematopoietic-stem-and-progenitor-cells
#11
Xiongwei Cai, Long Gao, Li Teng, Jingping Ge, Zaw Min Oo, Ashish R Kumar, D Gary Gilliland, Philip J Mason, Kai Tan, Nancy A Speck
The transcription factor RUNX1 is frequently mutated in myelodysplastic syndrome and leukemia. RUNX1 mutations can be early events, creating preleukemic stem cells that expand in the bone marrow. Here we show, counterintuitively, that Runx1-deficient hematopoietic stem and progenitor cells (HSPCs) have a slow growth, low biosynthetic, small cell phenotype and markedly reduced ribosome biogenesis (Ribi). The reduced Ribi involved decreased levels of rRNA and many mRNAs encoding ribosome proteins. Runx1 appears to directly regulate Ribi; Runx1 is enriched on the promoters of genes encoding ribosome proteins and binds the rDNA repeats...
August 6, 2015: Cell Stem Cell
https://www.readbyqxmd.com/read/25900776/induced-conformational-change-in-human-il-4-upon-binding-of-a-signal-neutralizing-darpin
#12
Galina Obmolova, Alexey Teplyakov, Thomas J Malia, Edward Keough, Jinquan Luo, Raymond Sweet, Steven A Jacobs, Fang Yi, Randi Hippensteel, Karyn T O'Neil, Gary L Gilliland
The crystal structure of DARPin 44C12V5 that neutralizes IL-4 signaling has been determined alone and bound to human IL-4. A significant conformational change occurs in the IL-4 upon DARPin binding. The DARPin binds to the face of IL-4 formed by the A and C α-helices. The structure of the DARPin remains virtually unchanged. The conformational changes in IL-4 include a reorientation of the C-helix Trp91 side chain and repositioning of CD-loop residue Leu96. Both side chains move by >9 Å, becoming buried in the central hydrophobic region of the IL-4:DARPin interface...
June 2015: Proteins
https://www.readbyqxmd.com/read/25593232/anti-carbamylated-protein-antibodies-are-present-prior-to-rheumatoid-arthritis-and-are-associated-with-its-future-diagnosis
#13
Ryan W Gan, Leendert A Trouw, Jing Shi, René E M Toes, Tom W J Huizinga, M Kristen Demoruelle, Jason R Kolfenbach, Gary O Zerbe, Kevin D Deane, Jess D Edison, William R Gilliland, Jill M Norris, V Michael Holers
OBJECTIVE: Anti-carbamylated protein (anti-CarP) antibodies could further elucidate early rheumatoid arthritis (RA) pathogenesis and predict clinical disease. We compared the diagnostic accuracy of anti-CarP antibodies for future RA to other RA-related antibodies in military personnel. METHODS: Stored pre-RA diagnosis serum samples from 76 RA cases were tested for anti-CarP fetal calf serum (FCS), anti-CarP fibrinogen (Fib), anticyclic citrullinated peptide antibodies version 2 (anti-CCP2), rheumatoid factor-nephelometry (RF-Neph), and RF isotypes [immunoglobulin M (IgM), IgG, and IgA]...
April 2015: Journal of Rheumatology
https://www.readbyqxmd.com/read/25534201/loss-of-c-cbl-e3-ubiquitin-ligase-activity-enhances-the-development-of-myeloid-leukemia-in-flt3-itd-mutant-mice
#14
Samuel J Taylor, Christine B F Thien, Samantha A Dagger, Johanna M Duyvestyn, Carolyn S Grove, Benjamin H Lee, D Gary Gilliland, Wallace Y Langdon
Mutations in the Fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase (RTK) occur frequently in acute myeloid leukemia (AML), with the most common involving internal tandem duplication (ITD) within the juxtamembrane domain. Fms-like tyrosine kinase 3-ITD mutations result in a mislocalized and constitutively activated receptor, which aberrantly phosphorylates signal transducer and activator of transcription 5 (STAT5) and upregulates the expression of its target genes. c-Cbl is an E3 ubiquitin ligase that negatively regulates RTKs, including FLT3, but whether it can downregulate mislocalized FLT3-ITD remains to be resolved...
March 2015: Experimental Hematology
https://www.readbyqxmd.com/read/25289887/mcl1-and-bcl-xl-levels-in-solid-tumors-are-predictive-of-dinaciclib-induced-apoptosis
#15
Robert N Booher, Harold Hatch, Brian M Dolinski, Thi Nguyen, Lauren Harmonay, Ali-Samer Al-Assaad, Mark Ayers, Michael Nebozhyn, Andrey Loboda, Heather A Hirsch, Theresa Zhang, Bin Shi, Carrie E Merkel, Minilik H Angagaw, Yaolin Wang, Brian J Long, Xianlu Q Lennon, Nathan Miselis, Vincenzo Pucci, James W Monahan, Junghoon Lee, Anna Georgieva Kondic, Eun Kyung Im, David Mauro, Rebecca Blanchard, Gary Gilliland, Stephen E Fawell, Leigh Zawel, Alwin G Schuller, Peter Strack
Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure...
2014: PloS One
https://www.readbyqxmd.com/read/25104330/discovery-of-biomarkers-predictive-of-gsi-response-in-triple-negative-breast-cancer-and-adenoid-cystic-carcinoma
#16
Alexander Stoeck, Serguei Lejnine, Andrew Truong, Li Pan, Hongfang Wang, Chongzhi Zang, Jing Yuan, Chris Ware, John MacLean, Philip W Garrett-Engele, Michael Kluk, Jason Laskey, Brian B Haines, Christopher Moskaluk, Leigh Zawel, Stephen Fawell, Gary Gilliland, Theresa Zhang, Brandon E Kremer, Birgit Knoechel, Bradley E Bernstein, Warren S Pear, X Shirley Liu, Jon C Aster, Sriram Sathyanarayanan
UNLABELLED: Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI...
October 2014: Cancer Discovery
https://www.readbyqxmd.com/read/25084393/protein-crystallization-with-microseed-matrix-screening-application-to-human-germline-antibody-fabs
#17
Galina Obmolova, Thomas J Malia, Alexey Teplyakov, Raymond W Sweet, Gary L Gilliland
The crystallization of 16 human antibody Fab fragments constructed from all pairs of four different heavy chains and four different light chains was enabled by employing microseed matrix screening (MMS). In initial screening, diffraction-quality crystals were obtained for only three Fabs, while many Fabs produced hits that required optimization. Application of MMS, using the initial screens and/or refinement screens, resulted in diffraction-quality crystals of these Fabs. Five Fabs that failed to give hits in the initial screen were crystallized by cross-seeding MMS followed by MMS optimization...
August 2014: Acta Crystallographica. Section F, Structural Biology Communications
https://www.readbyqxmd.com/read/24740812/integrated-genomic-analysis-illustrates-the-central-role-of-jak-stat-pathway-activation-in-myeloproliferative-neoplasm-pathogenesis
#18
Raajit Rampal, Fatima Al-Shahrour, Omar Abdel-Wahab, Jay P Patel, Jean-Philippe Brunel, Craig H Mermel, Adam J Bass, Jennifer Pretz, Jihae Ahn, Todd Hricik, Outi Kilpivaara, Martha Wadleigh, Lambert Busque, D Gary Gilliland, Todd R Golub, Benjamin L Ebert, Ross L Levine
Genomic studies have identified somatic alterations in the majority of myeloproliferative neoplasms (MPN) patients, including JAK2 mutations in the majority of MPN patients and CALR mutations in JAK2-negative MPN patients. However, the role of JAK-STAT pathway activation in different MPNs, and in patients without JAK2 mutations, has not been definitively delineated. We used expression profiling, single nucleotide polymorphism arrays, and mutational profiling to investigate a well-characterized cohort of MPN patients...
May 29, 2014: Blood
https://www.readbyqxmd.com/read/24668560/second-antibody-modeling-assessment-ama-ii
#19
Juan C Almagro, Alexey Teplyakov, Jinquan Luo, Raymond W Sweet, Sreekumar Kodangattil, Francisco Hernandez-Guzman, Gary L Gilliland
To assess the state of the art in antibody 3D modeling, 11 unpublished high-resolution x-ray Fab crystal structures from diverse species and covering a wide range of antigen-binding site conformations were used as a benchmark to compare Fv models generated by seven structure prediction methodologies. The participants included: Accerlys Inc, Chemical Computer Group (CCG), Schrodinger, Jeff Gray's lab at John Hopkins University, Macromoltek, Astellas Pharma/Osaka University and Prediction of ImmunoGlobulin Structure (PIGS)...
August 2014: Proteins
https://www.readbyqxmd.com/read/24638881/structure-and-specificity-of-an-antibody-targeting-a-proteolytically-cleaved-igg-hinge
#20
Thomas J Malia, Alexey Teplyakov, Randall J Brezski, Jinquan Luo, Michelle Kinder, Raymond W Sweet, Juan C Almagro, Robert E Jordan, Gary L Gilliland
The functional role of human antihinge (HAH) autoantibodies in normal health and disease remains elusive, but recent evidence supports their role in the host response to IgG cleavage by proteases that are prevalent in certain disorders. Characterization and potential exploitation of these HAH antibodies has been hindered by the absence of monoclonal reagents. 2095-2 is a rabbit monoclonal antibody targeting the IdeS-cleaved hinge of human IgG1. We have determined the crystal structure of the Fab of 2095-2 and its complex with a hinge analog peptide...
August 2014: Proteins
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