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Systems Pharmacology: An Overview [chapter]

Marc R. Birtwistle, Jens Hansen, James M. Gallo, Sreeharish Muppirisetty, Peter Man-Un Ung, Ravi Iyengar, Avner Schlessinger
2016 Systems Pharmacology and Pharmacodynamics  
KEGG also offers metabolic pathway maps on their website WikiPathways Further ontologies that associate genes with biological pathways Reactome pathway Online Mendelian Inheritance in Man (OMIM)  ...  2007) , developing covalent probes (Singh et al. 2011) , as well as by targeting allosteric or cryptic binding sites that cannot always be observed in a static X-ray structure doi:10.1002/bip.22742 (Ung  ... 
doi:10.1007/978-3-319-44534-2_4 fatcat:hnkzgvppa5ehjcqj65vw43fily

Redefining the Protein Kinase Conformational Space with Machine Learning

Peter Man-Un Ung, Rayees Rahman, Avner Schlessinger
2018 Cell Chemical Biology  
conformational space is expected to improve modeling of protein kinase structures, as well as guide the development of conformationspecific kinase inhibitors with optimal pharmacological profiles. eTOC BLURB Ung  ...  S3 in (Ung and Schlessinger, 2015) ).  ...  INTRODUCTION Protein kinases are important signaling molecules that constitute one of the largest drug target families in human (Manning et al., 2002; Schlessinger, 2014) .  ... 
doi:10.1016/j.chembiol.2018.05.002 pmid:29861272 pmcid:PMC6054563 fatcat:7l5hvickavcrrlyxbhqv3433xi

KinaMetrix: a web resource to investigate kinase conformations and inhibitor space

Rayees Rahman, Peter Man-Un Ung, Avner Schlessinger
2018 Nucleic Acids Research  
Protein kinases are among the most explored protein drug targets. Visualization of kinase conformations is critical for understanding structure-function relationship in this family and for developing chemically unique, conformation-specific small molecule drugs. We have developed Kinformation, a random forest classifier that annotates the conformation of over 3500 protein kinase structures in the Protein Data Bank. Kinformation was trained on structural descriptors derived from functionally
more » ... rtant motifs to automatically categorize kinases into five major conformations with pharmacological relevance. Here we present KinaMetrix (http://KinaMetrix.com), a web resource enabling researchers to investigate the protein kinase conformational space as well as a subset of kinase inhibitors that exhibit conformational specificity. KinaMetrix allows users to classify uploaded kinase structures, as well as to derive structural descriptors of protein kinases. Uploaded structures can then be compared to atomic structures of other kinases, enabling users to identify kinases that occupy a similar conformational space to their uploaded structure. Finally, KinaMetrix also serves as a repository for both small molecule substructures that are significantly associated with each conformation type, and for homology models of kinases in inactive conformations. We expect KinaMetrix to serve as a resource for researchers studying kinase structural biology or developing conformation-specific kinase inhibitors.
doi:10.1093/nar/gky916 pmid:30321373 pmcid:PMC6323924 fatcat:sycrxfivpbhuzd3bogfdlmfqgm

DFGmodel: Predicting Protein Kinase Structures in Inactive States for Structure-Based Discovery of Type-II Inhibitors

Peter Man-Un Ung, Avner Schlessinger
2015 Biophysical Journal  
(Supported by NIH grants TRO1DK087650 and P41GM103313) 2390-Pos Board B527 DFGmodel: Predicting Protein Kinase Structures in Inactive States for Structure-Based Discovery of Type-II Inhibitors Peter Man-Un  ...  Ung, Avner Schlessinger.  ...  (Supported by NIH grants TRO1DK087650 and P41GM103313) 2390-Pos Board B527 DFGmodel: Predicting Protein Kinase Structures in Inactive States for Structure-Based Discovery of Type-II Inhibitors Peter Man-Un  ... 
doi:10.1016/j.bpj.2014.11.2590 fatcat:xs6ku4isszbs7igjdvzqxzbisi

Integrated computational and Drosophila cancer model platform captures previously unappreciated chemicals perturbing a kinase network [article]

Peter Man-Un Ung, Masahiro Sonoshita, Alex P Scopton, Arvin C Dar, Ross L Cagan, Avner Schlessinger
2018 bioRxiv   pre-print
Ung PMU, Schlessinger A. DFGmodel: predicting protein kinase structures in inactive states for structure-based discovery of type-II inhibitors.  ...  DFG-model relies on a man-378 ually curated alignment between the target kinase and multiple structures representing379 unique DFG-out conformations.  ... 
doi:10.1101/344192 fatcat:ltcrro7jsjcf5j726e7goqoqqq

DFGmodel: Predicting Protein Kinase Structures in Inactive States for Structure-Based Discovery of Type-II Inhibitors

Peter Man-Un Ung, Avner Schlessinger
2014 ACS Chemical Biology  
Protein kinases exist in equilibrium of active and inactive states, in which the aspartate-phenylalanineglycine motif in the catalytic domain undergoes conformational changes that are required for function. Drugs targeting protein kinases typically bind the primary ATP-binding site of an active state (type-I inhibitors) or utilize an allosteric pocket adjacent to the ATP-binding site in the inactive state (type-II inhibitors). Limited crystallographic data of protein kinases in the inactive
more » ... e hampers the application of rational drug discovery methods for developing type-II inhibitors. Here, we present a computational approach to generate structural models of protein kinases in the inactive conformation. We first perform a comprehensive analysis of all protein kinase structures deposited in the Protein Data Bank. We then develop DFGmodel, a method that takes either a known structure of a kinase in the active conformation or a sequence of a kinase without a structure, to generate kinase models in the inactive conformation. Evaluation of DFGmodel's performance using various measures indicates that the inactive kinase models are accurate, exhibiting RMSD of 1.5 Å or lower. The kinase models also accurately distinguish type-II kinase inhibitors from likely nonbinders (AUC > 0.70), suggesting that they are useful for virtual screening. Finally, we demonstrate the applicability of our approach with three case studies. For example, the models are able to capture inhibitors with unintended off-target activity. Our computational approach provides a structural framework for chemical biologists to characterize kinases in the inactive state and to explore new chemical spaces with structure-based drug design. Protein kinases are highly dynamic. The N-lobe, αC-helix, hinge region, and A-loop can undergo a wide range of movement and adopt multiple conformations, such as DFG-flip and rotation of αC-helix, that define catalytic activity. 14−18 Particularly, the DFG-motif of protein kinases adopts two major conformations, including the DFG-in and DFG-out conformations, which are thought to determine active or inactive states, respectively, as well as various intermediate conformations. In the active state or DFG-in conformation, the DFG-Phe is packed into a hydrophobic pocket, the DFGpocket, between the N-and C-lobes, and stabilizes this active conformation through interactions with hydrophobic residues in that region. 19 In this conformation, the ATP-binding site is well-defined; the DFG-Asp faces outward to coordinate a magnesium ion for ATP binding, whereas the A-loop moves away from the ATP-binding site and forms a β-hairpin for substrate binding. Currently, there are 16 FDA-approved drugs that target the ATP-binding site in this conformation to
doi:10.1021/cb500696t pmid:25420233 pmcid:PMC4301084 fatcat:zqfujvzlvffrbmcvpqkhnxuzou

Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening

Peter Man-Un Ung, Wenxin Song, Lili Cheng, Xinbin Zhao, Hailin Hu, Ligong Chen, Avner Schlessinger
2016 ACS Chemical Biology  
transporter; cancer metabolism Recently, an atomic structure of the hGLUT1 has been determined in an inward-open conformation bound to a nonyl-β-D-glucoside inhibitor. 27 This structure confirmed that Ung  ...  Ung, Department of Defense (W81XWH-15-1-0539) to A. Schlessinger, and the National Natural Science Foundation of China (No. 81470839) to W. Song, L. Cheng, X. Zhao, H. Hu, and L. Chen.  ...  Tc value of < 0.35 suggests that the ligand is chemically novel hGLUT1 ligand Ung et al.  ... 
doi:10.1021/acschembio.6b00304 pmid:27128978 pmcid:PMC5356226 fatcat:qco6ghfj5fcnbarv3uzvig2vdi

Molecular Basis for Redox Activation of Epidermal Growth Factor Receptor Kinase

Thu H. Truong, Peter Man-Un Ung, Prakash B. Palde, Candice E. Paulsen, Avner Schlessinger, Kate S. Carroll
2016 Cell Chemical Biology  
EGFR is a target of signal-derived H 2 O 2 and oxidation of active site cysteine 797 to sulfenic acid enhances kinase activity. Although a major class of covalent drugs targets C797, nothing is known about its catalytic importance or how S-sulfenylation leads to activation. Here, we report the first detailed functional analysis of C797. In contrast to prior assumptions, mutation of C797 diminishes catalytic efficiency in vitro and cells. The experimentally determined pKa and reactivity of C797
more » ... owards H 2 O 2 correspondingly distinguish this residue from the bulk of the cysteinome. Molecular dynamic simulation of reduced versus oxidized EGFR, reinforced by experimental testing, indicates that sulfenylation of C797 allows new electrostatic interactions to be formed with the catalytic loop. Finally, we show that chronic oxidative stress yields an EGFR subpopulation that is refractory to the FDA-approved drug, afatinib. Collectively, our data highlight the significance of redox biology to understanding kinase regulation and drug pharmacology. eTOC BLURB Truong et al. elucidate the molecular mechanism underlying redox-activation of EGFR.
doi:10.1016/j.chembiol.2016.05.017 pmid:27427230 pmcid:PMC4958504 fatcat:el7tsqggzne57ihoaoesseanqe

GEN3VA: aggregation and analysis of gene expression signatures from related studies

Gregory W. Gundersen, Kathleen M. Jagodnik, Holly Woodland, Nicholas F. Fernandez, Kevin Sani, Anders B. Dohlman, Peter Man-Un Ung, Caroline D. Monteiro, Avner Schlessinger, Avi Ma'ayan
2016 BMC Bioinformatics  
Genome-wide gene expression profiling of mammalian cells is becoming a staple of many published biomedical and biological research studies. Such data is deposited into data repositories such as the Gene Expression Omnibus (GEO) for potential reuse. However, these repositories currently do not provide simple interfaces to systematically analyze collections of related studies. Results: Here we present GENE Expression and Enrichment Vector Analyzer (GEN3VA), a web-based system that enables the
more » ... grative analysis of aggregated collections of tagged gene expression signatures identified and extracted from GEO. Each tagged collection of signatures is presented in a report that consists of heatmaps of the differentially expressed genes; principal component analysis of all signatures; enrichment analysis with several gene set libraries across all signatures, which we term enrichment vector analysis; and global mapping of small molecules that are predicted to reverse or mimic each signature in the aggregate. We demonstrate how GEN3VA can be used to identify common molecular mechanisms of aging by analyzing tagged signatures from 244 studies that compared young vs. old tissues in mammalian systems. In a second case study, we collected 86 signatures from treatment of human cells with dexamethasone, a glucocorticoid receptor (GR) agonist. Our analysis confirms consensus GR target genes and predicts potential drug mimickers. Conclusions: GEN3VA can be used to identify, aggregate, and analyze themed collections of gene expression signatures from diverse but related studies. Such integrative analyses can be used to address concerns about data reproducibility, confirm results across labs, and discover new collective knowledge by data reuse. GEN3VA is an open-source web-based system that is freely available at: http://amp.pharm.mssm.edu/gen3va.
doi:10.1186/s12859-016-1321-1 pmid:27846806 pmcid:PMC5111283 fatcat:vlfpektbkfgtbnds2hafvwqd7a

Identification of Key Hinge Residues Important for Nucleotide-Dependent Allostery in E. coli Hsp70/DnaK

Peter Man-Un Ung, Andrea D. Thompson, Lyra Chang, Jason E. Gestwicki, Heather A. Carlson, Dennis R. Livesay
2013 PLoS Computational Biology  
DnaK is a molecular chaperone that has important roles in protein folding. The hydrolysis of ATP is essential to this activity, and the effects of nucleotides on the structure and function of DnaK have been extensively studied. However, the key residues that govern the conformational motions that define the apo, ATP-bound, and ADP-bound states are not entirely clear. Here, we used molecular dynamics simulations, mutagenesis, and enzymatic assays to explore the molecular basis of this process.
more » ... mulations of DnaK's nucleotide-binding domain (NBD) in the apo, ATP-bound, and ADP/P i -bound states suggested that each state has a distinct conformation, consistent with available biochemical and structural information. The simulations further suggested that large shearing motions between subdomains I-A and II-A dominated the conversion between these conformations. We found that several evolutionally conserved residues, especially G228 and G229, appeared to function as a hinge for these motions, because they predominantly populated two distinct states depending on whether ATP or ADP/P i was bound. Consistent with the importance of these "hinge" residues, alanine point mutations caused DnaK to have reduced chaperone activities in vitro and in vivo. Together, these results clarify how sub-domain motions communicate allostery in DnaK.
doi:10.1371/journal.pcbi.1003279 pmid:24277995 pmcid:PMC3836694 fatcat:hu7hk3xm2nccjdz6l3raxrd6ym

Identification of a G-Protein-Independent Activator of GIRK Channels

Yulin Zhao, Peter Man-Un Ung, Gergely Zahoránszky-Kőhalmi, Alexey V. Zakharov, Natalia J. Martinez, Anton Simeonov, Ian W. Glaaser, Ganesha Rai, Avner Schlessinger, Juan J. Marugan, Paul A. Slesinger
2020 Cell Reports  
G-protein-gated inwardly rectifying K+ (GIRK) channels are essential effectors of inhibitory neurotransmission in the brain. GIRK channels have been implicated in diseases with abnormal neuronal excitability, including epilepsy and addiction. GIRK channels are tetramers composed of either the same subunit (e.g., homotetramers) or different subunits (e.g., heterotetramers). Compounds that specifically target subsets of GIRK channels in vivo are lacking. Previous studies have shown that alcohol
more » ... rectly activates GIRK channels through a hydrophobic pocket located in the cytoplasmic domain of the channel. Here, we report the identification and functional characterization of a GIRK1-selective activator, termed GiGA1, that targets the alcohol pocket. GiGA1 activates GIRK1/GIRK2 both in vitro and in vivo and, in turn, mitigates the effects of a convulsant in an acute epilepsy mouse model. These results shed light on the structure-based development of subunit-specific GIRK modulators that could provide potential treatments for brain disorders.
doi:10.1016/j.celrep.2020.107770 pmid:32553165 pmcid:PMC7401321 fatcat:7s6vdeth3bf2rdjq2fthxksntq

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

Richard D. Smith, James B. Dunbar, Peter Man-Un Ung, Emilio X. Esposito, Chao-Yie Yang, Shaomeng Wang, Heather A. Carlson
2011 Journal of Chemical Information and Modeling  
doi:10.1021/ci200269q pmid:21809884 pmcid:PMC3186041 fatcat:o72lqwmrbbhgbh2pqtkxv6ifyq

CSAR Benchmark Exercise of 2010: Selection of the Protein–Ligand Complexes

James B. Dunbar, Richard D. Smith, Chao-Yie Yang, Peter Man-Un Ung, Katrina W. Lexa, Nickolay A. Khazanov, Jeanne A. Stuckey, Shaomeng Wang, Heather A. Carlson
2011 Journal of Chemical Information and Modeling  
doi:10.1021/ci200082t pmid:21728306 pmcid:PMC3180202 fatcat:cqd3oezs2bbdrlpz7spd75lxoq

An IRAK1–PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy

Peter H. Liu, Richa B. Shah, Yuanyuan Li, Arshi Arora, Peter Man-Un Ung, Renuka Raman, Andrej Gorbatenko, Shingo Kozono, Xiao Zhen Zhou, Vincent Brechin, John M. Barbaro, Ruth Thompson (+11 others)
2019 Nature Cell Biology  
Discussion The data presented here show that IRAK1 kinase, a core transducer in innate immune signaling conserved from flies to man 23, 24, 27 , plays an additional conserved role in the cell survival  ... 
doi:10.1038/s41556-018-0260-7 pmid:30664786 pmcid:PMC6428421 fatcat:qenivmznxbh4biym3wfmqiztr4

Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity

Ekaterina S. Kuzina, Peter Man-Un Ung, Jyotidarsini Mohanty, Francisco Tome, Jungyuen Choi, Els Pardon, Jan Steyaert, Irit Lax, Avner Schlessinger, Joseph Schlessinger, Sangwon Lee
2019 Proceedings of the National Academy of Sciences of the United States of America  
The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either α-Klotho or β-Klotho receptors. Structural analyses of ligand-occupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to β-Klotho or α-Klotho, respectively.
more » ... ey have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling. Here we describe the crystal structure the C-terminal tail of FGF19 (FGF19CT) bound to sKLB and demonstrate that FGF19CT and FGF21CT bind to the same binding site on sKLB, via a multiturn D-P motif to site 1 and via a S-P-S motif to the pseudoglycoside hydrolase region (site 2). Binding affinities to sKLB and cellular stimulatory activities of FGF19CT, FGF21CT, and a variety of chimeric mutants to cells expressing β-Klotho together with FGFR1c or FGFR4 were also analyzed. These experiments as well as detailed comparison of the structures of free and ligand-occupied sKLB to the structure of ligand-occupied sKLA reveal a general mechanism for recognition of endocrine FGFs by Klotho proteins and regulatory interactions with FGFRs that control their pleiotropic cellular responses.
doi:10.1073/pnas.1822055116 pmid:30944224 pmcid:PMC6475419 fatcat:mngq7vxvkvgavly6m2zlebgtme
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