Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2

Pádua, Ricardo A.  P.; Sun, Yizhi; Marko, Ingrid; Pitsawong, Warintra; Stiller, John B.; Otten, Renee; Kern, Dorothee

doi:10.1038/s41467-018-06814-w

Title: Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2

Journal Article · Tue Oct 30 00:00:00 EDT 2018 · Nature Communications

DOI:https://doi.org/10.1038/s41467-018-06814-w· OSTI ID:1624118

Pádua, Ricardo A. P. ^[1];

^[2]; Marko, Ingrid ^[1]; Pitsawong, Warintra ^[1]; Stiller, John B. ^[1];

^[1]; Kern, Dorothee ^[1]

Brandeis Univ., Waltham, MA (United States). Howard Hughes Medical Institute, Department of Biochemistry
Brandeis Univ., Waltham, MA (United States). Howard Hughes Medical Institute, Department of Biochemistry; Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (United States). Dept. of Cancer Biology and Cell Biology

Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations. Binding of the allosteric inhibitor SHP099 to E76K mutant, despite much weaker, results in an identical structure as the wild-type complex. A conformational selection to the closed state reduces drug affinity which, combined with E76K’s much higher activity, demands significantly greater SHP099 concentrations to restore wild-type activity levels. The differences in structural ensembles and drug-binding kinetics of cancer-associated SHP2 forms may stimulate innovative ideas for developing more potent inhibitors for activated SHP2 mutants.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231; AC02-76SF00515

OSTI ID:: 1624118

Journal Information:: Nature Communications, Vol. 9, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 60 works

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References (68)

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases Chen, Ying-Nan P.; LaMarche, Matthew J.; Chan, Ho Man Nature, Vol. 535, Issue 7610 https://doi.org/10.1038/nature18621	journal	June 2016
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor Garcia Fortanet, Jorge; Chen, Christine Hiu-Tung; Chen, Ying-Nan P. Journal of Medicinal Chemistry, Vol. 59, Issue 17 https://doi.org/10.1021/acs.jmedchem.6b00680	journal	July 2016
Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome Tartaglia, Marco; Mehler, Ernest L.; Goldberg, Rosalie Nature Genetics, Vol. 29, Issue 4 https://doi.org/10.1038/ng772	journal	November 2001
PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity Tartaglia, Marco; Kalidas, Kamini; Shaw, Adam The American Journal of Human Genetics, Vol. 70, Issue 6 https://doi.org/10.1086/340847	journal	June 2002
Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome Sarkozy, A. Journal of Medical Genetics, Vol. 41, Issue 5 https://doi.org/10.1136/jmg.2003.013466	journal	May 2004
Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia Tartaglia, Marco; Niemeyer, Charlotte M.; Fragale, Alessandra Nature Genetics, Vol. 34, Issue 2 https://doi.org/10.1038/ng1156	journal	April 2003
Determination of the catalytic activity of LEOPARD syndrome-associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling Noda, Saori; Takahashi, Atsushi; Hayashi, Takeru Biochemical and Biophysical Research Communications, Vol. 469, Issue 4 https://doi.org/10.1016/j.bbrc.2015.12.117	journal	January 2016
Crystal Structure of the Tyrosine Phosphatase SHP-2 Hof, Peter; Pluskey, Scott; Dhe-Paganon, Sirano Cell, Vol. 92, Issue 4 https://doi.org/10.1016/S0092-8674(00)80938-1	journal	February 1998
Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2 Barford, David; Neel, Benjamin G. Structure, Vol. 6, Issue 3 https://doi.org/10.1016/S0969-2126(98)00027-6	journal	March 1998
Diversity and Functional Consequences of Germline and Somatic PTPN11 Mutations in Human Disease Tartaglia, Marco; Martinelli, Simone; Stella, Lorenzo The American Journal of Human Genetics, Vol. 78, Issue 2 https://doi.org/10.1086/499925	journal	February 2006
Diverse Biochemical Properties of Shp2 Mutants: IMPLICATIONS FOR DISEASE PHENOTYPES Keilhack, Heike; David, Frank S.; McGregor, Malcolm Journal of Biological Chemistry, Vol. 280, Issue 35 https://doi.org/10.1074/jbc.M504699200	journal	June 2005
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations Mohi, M. Golam; Williams, Ifor R.; Dearolf, Charles R. Cancer Cell, Vol. 7, Issue 2 https://doi.org/10.1016/j.ccr.2005.01.010	journal	February 2005
Upregulation of Src homology phosphotyrosyl phosphatase 2 (Shp2) expression in oral cancer and knockdown of Shp2 expression inhibit tumor cell viability and invasion in vitro Xie, Hongjun; Huang, Shengyun; Li, Wengang Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology, Vol. 117, Issue 2 https://doi.org/10.1016/j.oooo.2013.10.018	journal	February 2014
Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11) Qiu, Wei; Wang, Xiaonan; Romanov, Vladimir BMC Structural Biology, Vol. 14, Issue 1 https://doi.org/10.1186/1472-6807-14-10	journal	January 2014
Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2 LaRochelle, Jonathan R.; Fodor, Michelle; Xu, Xiang Biochemistry, Vol. 55, Issue 15 https://doi.org/10.1021/acs.biochem.5b01287	journal	April 2016
Transgenic Drosophila models of Noonan syndrome causing PTPN11 gain-of-function mutations Oishi, Kimihiko; Gaengel, Konstantin; Krishnamoorthy, Srinivasan Human Molecular Genetics, Vol. 15, Issue 4 https://doi.org/10.1093/hmg/ddi471	journal	January 2006
Differential Mechanisms for SHP2 Binding and Activation Are Exploited by Geographically Distinct Helicobacter pylori CagA Oncoproteins Hayashi, Takeru; Senda, Miki; Suzuki, Nobuhiro Cell Reports, Vol. 20, Issue 12 https://doi.org/10.1016/j.celrep.2017.08.080	journal	September 2017
A widely expressed human protein-tyrosine phosphatase containing src homology 2 domains. Ahmad, S.; Banville, D.; Zhao, Z. Proceedings of the National Academy of Sciences, Vol. 90, Issue 6 https://doi.org/10.1073/pnas.90.6.2197	journal	March 1993
Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation Wang, Wei; Liu, Lijun; Song, Xi Journal of Cellular Biochemistry, Vol. 112, Issue 8 https://doi.org/10.1002/jcb.23125	journal	July 2011
Conformational Motions Regulate Phosphoryl Transfer in Related Protein Tyrosine Phosphatases Whittier, S. K.; Hengge, A. C.; Loria, J. P. Science, Vol. 341, Issue 6148 https://doi.org/10.1126/science.1241735	journal	August 2013
Insights into the Reaction of Protein-tyrosine Phosphatase 1B: CRYSTAL STRUCTURES FOR TRANSITION STATE ANALOGS OF BOTH CATALYTIC STEPS Brandão, Tiago A. S.; Hengge, Alvan C.; Johnson, Sean J. Journal of Biological Chemistry, Vol. 285, Issue 21 https://doi.org/10.1074/jbc.M109.066951	journal	March 2010
Conformational selection or induced fit: A flux description of reaction mechanism Hammes, G. G.; Chang, Y. -C.; Oas, T. G. Proceedings of the National Academy of Sciences, Vol. 106, Issue 33 https://doi.org/10.1073/pnas.0907195106	journal	July 2009
Conformational Selection in a Protein-Protein Interaction Revealed by Dynamic Pathway Analysis Chakrabarti, Kalyan S.; Agafonov, Roman V.; Pontiggia, Francesco Cell Reports, Vol. 14, Issue 1 https://doi.org/10.1016/j.celrep.2015.12.010	journal	January 2016
Conformational selection in protein binding and function: Conformational Selection Weikl, Thomas R.; Paul, Fabian Protein Science, Vol. 23, Issue 11 https://doi.org/10.1002/pro.2539	journal	September 2014
Cloning, Expression and Mutational Analysis of SH-PTP2, Human Protein-Tyrosine Phosphatase Bastien, L.; Ramachandran, C.; Liu, S. Biochemical and Biophysical Research Communications, Vol. 196, Issue 1 https://doi.org/10.1006/bbrc.1993.2224	journal	October 1993
Assay to visualize specific protein oxidation reveals spatio-temporal regulation of SHP2 Tsutsumi, Ryouhei; Harizanova, Jana; Stockert, Rabea Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00503-w	journal	September 2017
The structure of apo protein-tyrosine phosphatase 1B C215S mutant: More than just an S → O change Scapin, Giovanna; Patel, Sangita; Patel, Vira Protein Science, Vol. 10, Issue 8 https://doi.org/10.1110/ps.11001	journal	August 2001
Energetic dissection of Gleevec's selectivity toward human tyrosine kinases Agafonov, Roman V.; Wilson, Christopher; Otten, Renee Nature Structural & Molecular Biology, Vol. 21, Issue 10 https://doi.org/10.1038/nsmb.2891	journal	September 2014
The drug–target residence time model: a 10-year retrospective Copeland, Robert A. Nature Reviews Drug Discovery, Vol. 15, Issue 2 https://doi.org/10.1038/nrd.2015.18	journal	December 2015
Drug–target residence time and its implications for lead optimization Copeland, Robert A.; Pompliano, David L.; Meek, Thomas D. Nature Reviews Drug Discovery, Vol. 5, Issue 9 https://doi.org/10.1038/nrd2082	journal	August 2006
Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery Choy, Meng S.; Li, Yang; Machado, Luciana E. S. F. Molecular Cell, Vol. 65, Issue 4 https://doi.org/10.1016/j.molcel.2017.01.014	journal	February 2017
Dual Allosteric Inhibition of SHP2 Phosphatase Fodor, Michelle; Price, Edmund; Wang, Ping ACS Chemical Biology, Vol. 13, Issue 3 https://doi.org/10.1021/acschembio.7b00980	journal	January 2018
The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1 Wylie, Andrew A.; Schoepfer, Joseph; Jahnke, Wolfgang Nature, Vol. 543, Issue 7647 https://doi.org/10.1038/nature21702	journal	March 2017
Global Kinetic Explorer: A new computer program for dynamic simulation and fitting of kinetic data Johnson, Kenneth A.; Simpson, Zachary B.; Blom, Thomas Analytical Biochemistry, Vol. 387, Issue 1 https://doi.org/10.1016/j.ab.2008.12.024	journal	April 2009
iMOSFLM : a new graphical interface for diffraction-image processing with MOSFLM Battye, T. Geoff G.; Kontogiannis, Luke; Johnson, Owen Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910048675	journal	March 2011
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
UCSF Chimera?A visualization system for exploratory research and analysis Pettersen, Eric F.; Goddard, Thomas D.; Huang, Conrad C. Journal of Computational Chemistry, Vol. 25, Issue 13 https://doi.org/10.1002/jcc.20084	journal	January 2004
ATSAS 2.8 : a comprehensive data analysis suite for small-angle scattering from macromolecular solutions Franke, D.; Petoukhov, M. V.; Konarev, P. V. Journal of Applied Crystallography, Vol. 50, Issue 4 https://doi.org/10.1107/S1600576717007786	journal	June 2017
Comparative Protein Modelling by Satisfaction of Spatial Restraints Šali, Andrej; Blundell, Tom L. Journal of Molecular Biology, Vol. 234, Issue 3 https://doi.org/10.1006/jmbi.1993.1626	journal	December 1993
Putting the Pieces Together: Integrative Modeling Platform Software for Structure Determination of Macromolecular Assemblies Russel, Daniel; Lasker, Keren; Webb, Ben PLoS Biology, Vol. 10, Issue 1 https://doi.org/10.1371/journal.pbio.1001244	journal	January 2012
Accurate SAXS Profile Computation and its Assessment by Contrast Variation Experiments Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A. Biophysical Journal, Vol. 105, Issue 4 https://doi.org/10.1016/j.bpj.2013.07.020	journal	August 2013
FoXS, FoXSDock and MultiFoXS: Single-state and multi-state structural modeling of proteins and their complexes based on SAXS profiles Schneidman-Duhovny, Dina; Hammel, Michal; Tainer, John A. Nucleic Acids Research, Vol. 44, Issue W1 https://doi.org/10.1093/nar/gkw389	journal	May 2016
Structure-based model of allostery predicts coupling between distant sites Weinkam, P.; Pons, J.; Sali, A. Proceedings of the National Academy of Sciences, Vol. 109, Issue 13 https://doi.org/10.1073/pnas.1116274109	journal	March 2012
Outcome of a Workshop on Applications of Protein Models in Biomedical Research Schwede, Torsten; Sali, Andrej; Honig, Barry Structure, Vol. 17, Issue 2 https://doi.org/10.1016/j.str.2008.12.014	journal	February 2009
SASBDB, a repository for biological small-angle scattering data Valentini, Erica; Kikhney, Alexey G.; Previtali, Gianpietro Nucleic Acids Research, Vol. 43, Issue D1 https://doi.org/10.1093/nar/gku1047	journal	October 2014
2017 publication guidelines for structural modelling of small-angle scattering data from biomolecules in solution: an update Trewhella, Jill; Duff, Anthony P.; Durand, Dominique Acta Crystallographica Section D Structural Biology, Vol. 73, Issue 9 https://doi.org/10.1107/S2059798317011597	journal	August 2017
The CCPN data model for NMR spectroscopy: Development of a software pipeline Vranken, Wim F.; Boucher, Wayne; Stevens, Tim J. Proteins: Structure, Function, and Bioinformatics, Vol. 59, Issue 4 https://doi.org/10.1002/prot.20449	journal	April 2005
TROSY in triple-resonance experiments: New perspectives for sequential NMR assignment of large proteins Salzmann, M.; Pervushin, K.; Wider, G. Proceedings of the National Academy of Sciences, Vol. 95, Issue 23 https://doi.org/10.1073/pnas.95.23.13585	journal	November 1998
Gradient-Enhanced Triple-Resonance Three-Dimensional NMR Experiments with Improved Sensitivity Muhandiram, D. R.; Kay, L. E. Journal of Magnetic Resonance, Series B, Vol. 103, Issue 3 https://doi.org/10.1006/jmrb.1994.1032	journal	March 1994
Single Scan, Sensitivity- and Gradient-Enhanced TROSY for Multidimensional NMR Experiments Weigelt, Johan Journal of the American Chemical Society, Vol. 120, Issue 41 https://doi.org/10.1021/ja982649y	journal	October 1998
BioMagResBank Ulrich, E. L.; Akutsu, H.; Doreleijers, J. F. Nucleic Acids Research, Vol. 36, Issue Database https://doi.org/10.1093/nar/gkm957	journal	December 2007
The Projection Analysis of NMR Chemical Shifts Reveals Extended EPAC Autoinhibition Determinants Selvaratnam, Rajeevan; VanSchouwen, Bryan; Fogolari, Federico Biophysical Journal, Vol. 102, Issue 3 https://doi.org/10.1016/j.bpj.2011.12.030	journal	February 2012
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Hinge-shift mechanism as a protein design principle for the evolution of β-lactamases from substrate promiscuity to specificity Modi, Tushar; Risso, Valeria A.; Martinez-Rodriguez, Sergio Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-22089-0	journal	March 2021
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-021-81903-3	journal	January 2021
Single Transition-to-single Transition Polarization Transfer (ST2-PT) in [15N,1H]-TROSY Pervushin, Konstantin V.; Wider, Gerhard; Wüthrich, Kurt ETH Zurich https://doi.org/10.3929/ethz-b-000422786	text	January 1998
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Restoring Low Resolution Structure of Biological Macromolecules from Solution Scattering Using Simulated Annealing Svergun, D. I. Biophysical Journal, Vol. 76, Issue 6, p. 2879-2886 https://doi.org/10.1016/s0006-3495(99)77443-6	journal	June 1999
The ‘Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling Neel, Benjamin G.; Gu, Haihua; Pao, Lily Trends in Biochemical Sciences, Vol. 28, Issue 6 https://doi.org/10.1016/s0968-0004(03)00091-4	journal	June 2003
Structure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1 McClelland, Levi J.; Zhang, Kaiming; Mou, Tung-Chung Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-14943-4	journal	February 2020
Structural and Mechanistic Insights into LEOPARD Syndrome-Associated SHP2 Mutations Yu, Zhi-Hong; Xu, Jie; Walls, Chad D. Journal of Biological Chemistry, Vol. 288, Issue 15 https://doi.org/10.1074/jbc.m113.450023	journal	March 2013
Water-molecule network and active-site flexibility of apo protein tyrosine phosphatase 1B Pedersen, Anja K.; Peters, Günther H.; Møller, Karin B. Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 9 https://doi.org/10.1107/s0907444904015094	journal	August 2004
Space-group and origin ambiguity in macromolecular structures with pseudo-symmetry and its treatment with the program Zanuda Lebedev, Andrey A.; Isupov, Michail N. Acta Crystallographica Section D Biological Crystallography, Vol. 70, Issue 9 https://doi.org/10.1107/s1399004714014795	journal	August 2014
ACHESYM : an algorithm and server for standardized placement of macromolecular models in the unit cell Kowiel, Marcin; Jaskolski, Mariusz; Dauter, Zbigniew Acta Crystallographica Section D Biological Crystallography, Vol. 70, Issue 12 https://doi.org/10.1107/s1399004714024572	journal	November 2014
SAXS Merge : an automated statistical method to merge SAXS profiles using Gaussian processes Spill, Yannick G.; Kim, Seung Joong; Schneidman-Duhovny, Dina Journal of Synchrotron Radiation, Vol. 21, Issue 1 https://doi.org/10.1107/s1600577513030117	journal	December 2013
An expanded allosteric network in PTP1B by multitemperature crystallography, fragment screening, and covalent tethering Keedy, Daniel A.; Hill, Zachary B.; Biel, Justin T. eLife, Vol. 7 https://doi.org/10.7554/elife.36307	journal	June 2018

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