Octahedral Trifluoromagnesate, an Anomalous Metal Fluoride Species, Stabilizes the Transition State in a Biological Motor

Overview

Journal ACS Catal

Publisher American Chemical Society

Date 2021 Mar 15

PMID 33717640

Citations 4

Authors

Mengyu Ge

Robert W Molt Jr

Huw T Jenkins

G Michael Blackburn

Yi Jin

Alfred A Antson

Affiliations

Soon will be listed here.

Abstract

Isoelectronic metal fluoride transition state analogue (TSA) complexes, MgF and AlF , have proven to be immensely useful in understanding mechanisms of biological motors utilizing phosphoryl transfer. Here we report a previously unobserved octahedral TSA complex, MgF(HO), in a 1.5 Å resolution Zika virus NS3 helicase crystal structure. F NMR provided independent validation and also the direct observation of conformational tightening resulting from ssRNA binding in solution. The TSA stabilizes the two conformations of motif V of the helicase that link ATP hydrolysis with mechanical work. DFT analysis further validated the MgF(HO) species, indicating the significance of this TSA for studies of biological motors.

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References

Baxter N, Olguin L, Golicnik M, Feng G, Hounslow A, Bermel W . A Trojan horse transition state analogue generated by MgF3- formation in an enzyme active site. Proc Natl Acad Sci U S A. 2006; 103(40):14732-7. PMC: 1595420. DOI: 10.1073/pnas.0604448103. View

Schramm V . Transition States, analogues, and drug development. ACS Chem Biol. 2012; 8(1):71-81. PMC: 3560411. DOI: 10.1021/cb300631k. View

Graham D, Lowe P, Grime G, Marsh M, Rittinger K, Smerdon S . MgF(3)(-) as a transition state analog of phosphoryl transfer. Chem Biol. 2002; 9(3):375-81. DOI: 10.1016/s1074-5521(02)00112-6. View

Kumar D, Aarthy M, Kumar P, Singh S, Uversky V, Giri R . Targeting the NTPase site of Zika virus NS3 helicase for inhibitor discovery. J Biomol Struct Dyn. 2019; 38(16):4827-4837. DOI: 10.1080/07391102.2019.1689851. View

Sampath A, Xu T, Chao A, Luo D, Lescar J, Vasudevan S . Structure-based mutational analysis of the NS3 helicase from dengue virus. J Virol. 2006; 80(13):6686-90. PMC: 1488930. DOI: 10.1128/JVI.02215-05. View

Badshah S, Ahmad N, Rehman A, Khan K, Ullah A, Alsayari A . Molecular docking and simulation of Zika virus NS3 helicase. BMC Chem. 2019; 13(1):67. PMC: 6661806. DOI: 10.1186/s13065-019-0582-y. View

Tanner N, Linder P . DExD/H box RNA helicases: from generic motors to specific dissociation functions. Mol Cell. 2001; 8(2):251-62. DOI: 10.1016/s1097-2765(01)00329-x. View

Myong S, Bruno M, Pyle A, Ha T . Spring-loaded mechanism of DNA unwinding by hepatitis C virus NS3 helicase. Science. 2007; 317(5837):513-6. PMC: 3565428. DOI: 10.1126/science.1144130. View

Jia Z, Yan L, Ren Z, Wu L, Wang J, Guo J . Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis. Nucleic Acids Res. 2019; 47(12):6538-6550. PMC: 6614802. DOI: 10.1093/nar/gkz409. View

10.

Jin Y, Molt Jr R, Pellegrini E, Cliff M, Bowler M, Richards N . Assessing the Influence of Mutation on GTPase Transition States by Using X-ray Crystallography, F NMR, and DFT Approaches. Angew Chem Int Ed Engl. 2017; 56(33):9732-9735. PMC: 5575484. DOI: 10.1002/anie.201703074. View

11.

Yang X, Chen C, Tian H, Chi H, Mu Z, Zhang T . Mechanism of ATP hydrolysis by the Zika virus helicase. FASEB J. 2018; 32(10):5250-5257. DOI: 10.1096/fj.201701140R. View

12.

Jin Y, Cliff M, Baxter N, Dannatt H, Hounslow A, Bowler M . Charge-balanced metal fluoride complexes for protein kinase A with adenosine diphosphate and substrate peptide SP20. Angew Chem Int Ed Engl. 2012; 51(49):12242-5. DOI: 10.1002/anie.201204266. View

13.

Gu M, Rice C . Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism. Proc Natl Acad Sci U S A. 2010; 107(2):521-8. PMC: 2818896. DOI: 10.1073/pnas.0913380107. View

14.

Baxter N, Blackburn G, Marston J, Hounslow A, Cliff M, Bermel W . Anionic charge is prioritized over geometry in aluminum and magnesium fluoride transition state analogs of phosphoryl transfer enzymes. J Am Chem Soc. 2008; 130(12):3952-8. DOI: 10.1021/ja078000n. View

15.

Cliff M, Bowler M, Varga A, Marston J, Szabo J, Hounslow A . Transition state analogue structures of human phosphoglycerate kinase establish the importance of charge balance in catalysis. J Am Chem Soc. 2010; 132(18):6507-16. DOI: 10.1021/ja100974t. View

16.

Hoepfner V, Deringer V, Dronskowski R . Hydrogen-bonding networks from first-principles: exploring the guanidine crystal. J Phys Chem A. 2012; 116(18):4551-9. DOI: 10.1021/jp2106132. View

17.

Jin Y, Bhattasali D, Pellegrini E, Forget S, Baxter N, Cliff M . α-Fluorophosphonates reveal how a phosphomutase conserves transition state conformation over hexose recognition in its two-step reaction. Proc Natl Acad Sci U S A. 2014; 111(34):12384-9. PMC: 4151737. DOI: 10.1073/pnas.1402850111. View

18.

Kamerlin S, Sharma P, Prasad R, Warshel A . Why nature really chose phosphate. Q Rev Biophys. 2013; 46(1):1-132. PMC: 7032660. DOI: 10.1017/S0033583512000157. View

19.

Luo D, Vasudevan S, Lescar J . The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development. Antiviral Res. 2015; 118:148-58. DOI: 10.1016/j.antiviral.2015.03.014. View

20.

Jean N, Rutherford T, Lowe J . FtsK in motion reveals its mechanism for double-stranded DNA translocation. Proc Natl Acad Sci U S A. 2020; 117(25):14202-14208. PMC: 7321959. DOI: 10.1073/pnas.2001324117. View