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"To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation.

Kovalevsky A, Aggarwal M, Velazquez H, Cuneo MJ, Blakeley MP, Weiss KL, Smith JC, Fisher SZ, McKenna R
Structure 26 383-390.e3 (2018)
Related entries: 6bc9, 6bcc

Cited: 18 times
EuropePMC logo PMID: 29429876

Abstract

Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.

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  3. Visualizing drug binding interactions using microcrystal electron diffraction. Clabbers MTB, Fisher SZ, Coinçon M, Zou X, Xu H. Commun Biol 3 417 (2020)
  4. Sulfamoyl Heteroarylcarboxylic Acids as Promising Metallo-β-Lactamase Inhibitors for Controlling Bacterial Carbapenem Resistance. Wachino JI, Jin W, Kimura K, Kurosaki H, Sato A, Arakawa Y. mBio 11 e03144-19 (2020)
  5. Productive reorientation of a bound oxime reactivator revealed in room temperature X-ray structures of native and VX-inhibited human acetylcholinesterase. Gerlits O, Kong X, Cheng X, Wymore T, Blumenthal DK, Taylor P, Radić Z, Kovalevsky A. J Biol Chem 294 10607-10618 (2019)
  6. Structure and mechanism of secondary sulfonamide binding to carbonic anhydrases. Baronas D, Dudutienė V, Paketurytė V, Kairys V, Smirnov A, Juozapaitienė V, Vaškevičius A, Manakova E, Gražulis S, Zubrienė A, Matulis D. Eur Biophys J 50 993-1011 (2021)
  7. Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase. Ali A, Ali A, Warsi MH, Rahman MA, Ahsan MJ, Azam F. Int J Mol Sci 23 5054 (2022)
  8. Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors. Kazokaitė J, Kairys V, Smirnovienė J, Smirnov A, Manakova E, Tolvanen M, Parkkila S, Matulis D. Sci Rep 9 12710 (2019)
  9. Isoform-Selective Enzyme Inhibitors by Exploring Pocket Size According to the Lock-and-Key Principle. Dudutienė V, Zubrienė A, Kairys V, Smirnov A, Smirnovienė J, Leitans J, Kazaks A, Tars K, Manakova L, Gražulis S, Matulis D. Biophys J 119 1513-1524 (2020)
  10. Native mass spectrometry of human carbonic anhydrase I and its inhibitor complexes. Zoppi C, Nocentini A, Supuran CT, Pratesi A, Messori L. J Biol Inorg Chem 25 979-993 (2020)
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  12. Beta and Gamma Amino Acid-Substituted Benzenesulfonamides as Inhibitors of Human Carbonic Anhydrases. Balandis B, Šimkūnas T, Paketurytė-Latvė V, Michailovienė V, Mickevičiūtė A, Manakova E, Gražulis S, Belyakov S, Kairys V, Mickevičius V, Zubrienė A, Matulis D. Pharmaceuticals (Basel) 15 477 (2022)
  13. Temperature-Induced Replacement of Phosphate Proton with Metal Ion Captured in Neutron Structures of A-DNA. Vandavasi VG, Blakeley MP, Keen DA, Hu LR, Huang Z, Kovalevsky A. Structure 26 1645-1650.e3 (2018)
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  15. What are the current limits on determination of protonation state using neutron macromolecular crystallography? Liebschner D, Afonine PV, Moriarty NW, Adams PD. Methods Enzymol 634 225-255 (2020)


Related citations provided by authors (1)

  1. Generalized X-ray and neutron crystallographic analysis: more accurate and complete structures for biological macromolecules.. Adams PD, Mustyakimov M, Afonine PV, Langan P Acta Crystallogr D Biol Crystallogr 65 567-73 (2009)

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