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Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery.

Choy MS, Li Y, Machado LESF, Kunze MBA, Connors CR, Wei X, Lindorff-Larsen K, Page R, Peti W
Mol Cell 65 644-658.e5 (2017)
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Cited: 53 times
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Abstract

Protein function originates from a cooperation of structural rigidity, dynamics at different timescales, and allostery. However, how these three pillars of protein function are integrated is still only poorly understood. Here we show how these pillars are connected in Protein Tyrosine Phosphatase 1B (PTP1B), a drug target for diabetes and cancer that catalyzes the dephosphorylation of numerous substrates in essential signaling pathways. By combining new experimental and computational data on WT-PTP1B and ≥10 PTP1B variants in multiple states, we discovered a fundamental and evolutionarily conserved CH/π switch that is critical for positioning the catalytically important WPD loop. Furthermore, our data show that PTP1B uses conformational and dynamic allostery to regulate its activity. This shows that both conformational rigidity and dynamics are essential for controlling protein activity. This connection between rigidity and dynamics at different timescales is likely a hallmark of all enzyme function.

Articles - 5ka0 mentioned but not cited (2)

  1. Conformational Rigidity and Protein Dynamics at Distinct Timescales Regulate PTP1B Activity and Allostery. Choy MS, Li Y, Machado LESF, Kunze MBA, Connors CR, Wei X, Lindorff-Larsen K, Page R, Peti W. Mol Cell 65 644-658.e5 (2017)
  2. research-article Native dynamics and allosteric responses in PTP1B probed by high-resolution HDX-MS. Woods VA, Abzalimov RR, Keedy DA. bioRxiv 2023.07.12.548582 (2023)


Reviews citing this publication (6)

  1. Turn and Face the Strange: A New View on Phosphatases. Köhn M. ACS Cent Sci 6 467-477 (2020)
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  6. The influence of random-coil chemical shifts on the assessment of structural propensities in folded proteins and IDPs. Kovács D, Bodor A. RSC Adv 13 10182-10203 (2023)

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  14. The mode of action of the Protein tyrosine phosphatase 1B inhibitor Ertiprotafib. Kumar GS, Page R, Peti W. PLoS One 15 e0240044 (2020)
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  22. Mechanistic roles of tyrosine phosphorylation in reversible amyloids, autoinhibition, and endosomal membrane association of ALIX. Elias RD, Ramaraju B, Deshmukh L. J Biol Chem 297 101328 (2021)
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  30. Letter Discovery and Validation of the Binding Poses of Allosteric Fragment Hits to Protein Tyrosine Phosphatase 1b: From Molecular Dynamics Simulations to X-ray Crystallography. Greisman JB, Willmore L, Yeh CY, Giordanetto F, Shahamadtar S, Nisonoff H, Maragakis P, Shaw DE. J Chem Inf Model 63 2644-2650 (2023)
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  33. Direct Intracellular Delivery of Benzene Diazonium Ions As Observed by Increased Tyrosine Phosphorylation. Cornejo NR, Amofah B, Lipinski A, Langlais PR, Ghosh I, Jewett JC. Biochemistry 61 656-664 (2022)
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  37. An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol. Shi T, Wijeratne EMK, Solano C, Ambrose AJ, Ross AB, Norwood C, Orido CK, Grigoryan T, Tillotson J, Kang M, Luo G, Keegan BM, Hu W, Hu W, Blagg BSJ, Zhang DD, Gunatilaka AAL, Chapman E. Biochemistry 58 3225-3231 (2019)
  38. Assessment of Flexible Shape Complementarity: New Opportunities to Explain and Induce Selectivity in Ligands of Protein Tyrosine Phosphatase 1B. Naß A, Schaller D, Wolber G. Mol Inform 38 e1800141 (2019)
  39. Biophysical Rationale for the Selective Inhibition of PTP1B over TCPTP by Nonpolar Terpenoids. Friedman AJ, Padgette HM, Kramer L, Liechty ET, Donovan GW, Fox JM, Shirts MR. J Phys Chem B 127 8305-8316 (2023)
  40. Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators. Hardie A, Cossins BP, Lovera S, Michel J. Commun Chem 6 125 (2023)
  41. Dynamic Long-Range Interactions Influence Substrate Binding and Catalysis by Human Histidine Triad Nucleotide-Binding Proteins (HINTs), Key Regulators of Multiple Cellular Processes and Activators of Antiviral ProTides. Strom A, Shah R, Dolot R, Rogers MS, Tong CL, Wang D, Xia Y, Lipscomb JD, Wagner CR. Biochemistry 61 2648-2661 (2022)
  42. Macromolecular crowding amplifies allosteric regulation of T-cell protein tyrosine phosphatase. Tun MT, Yang S, Forti FL, Santelli E, Bottini N. J Biol Chem 298 102655 (2022)
  43. Mapping the Chemical Space of Active-Site Targeted Covalent Ligands for Protein Tyrosine Phosphatases. Hong SH, Xi SY, Johns AC, Tang LC, Li A, Hum MN, Chartier CA, Jovanovic M, Shah NH. Chembiochem 24 e202200706 (2023)
  44. Protein Conformational Space at the Edge of Allostery: Turning a Nonallosteric Malate Dehydrogenase into an "Allosterized" Enzyme Using Evolution-Guided Punctual Mutations. Iorio A, Brochier-Armanet C, Mas C, Sterpone F, Madern D. Mol Biol Evol 39 msac186 (2022)
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