Structure and dynamics of the G121V Dihydrofolate reductase mutant: Lessons from a transition-state inhibitor complex

PLoS ONE

Volumn 7, Issue 3, 2012, Pages

  Mauldin, Randall V ^a   Sapienza, Paul J ^b   Petit, Chad M ^b   Lee, Andrew L ^a,b  

^a UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^b University of North Carolina   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE; DIHYDROFOLATE REDUCTASE; METHIONINE; METHOTREXATE; NITROGEN 15; PROTON; NITROGEN;

ARTICLE; ENZYME ACTIVE SITE; ENZYME CONFORMATION; ENZYME MECHANISM; ENZYME STRUCTURE; GENE MUTATION; MOLECULAR DYNAMICS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PROTEIN BINDING; PROTEIN DOMAIN; PROTON NUCLEAR MAGNETIC RESONANCE; ANISOTROPY; CHEMICAL STRUCTURE; CHEMISTRY; GENETICS; METABOLISM; MISSENSE MUTATION; NUCLEAR MAGNETIC RESONANCE; PROTEIN CONFORMATION; TIME;

ANISOTROPY; METHOTREXATE; MODELS, MOLECULAR; MUTATION, MISSENSE; NITROGEN ISOTOPES; NUCLEAR MAGNETIC RESONANCE, BIOMOLECULAR; PROTEIN CONFORMATION; TETRAHYDROFOLATE DEHYDROGENASE; TIME FACTORS;

EID: 84858121090     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0033252     Document Type: Article

References (47)

1. Wolfenden R, (2003) Thermodynamic and extrathermodynamic requirements of enzyme catalysis. Biophys Chem 105: 559-572.
2. Boehr DD, McElheny D, Dyson HJ, Wright PE, (2006) The dynamic energy landscape of dihydrofolate reductase catalysis. Science 313: 1638-1642.
3. Eisenmesser EZ, Bosco DA, Akke M, Kern D, (2002) Enzyme dynamics during catalysis. Science 295: 1520-1523.
4. Watt ED, Shimada H, Kovrigin EL, Loria JP, (2007) The mechanism of rate-limiting motions in enzyme function. Proc Natl Acad Sci U S A 104: 11981-11986.
5. Eisenmesser EZ, Millet O, Labeikovsky W, Korzhnev DM, Wolf-Watz M, et al. (2005) Intrinsic dynamics of an enzyme underlies catalysis. Nature 438: 117-121.
6. Bhabha G, Lee J, Ekiert DC, Gam J, Wilson IA, et al. (2011) A dynamic knockout reveals that conformational fluctuations influence the chemical step of enzyme catalysis. Science 332: 234-238.
7. Nashine VC, Hammes-Schiffer S, Benkovic SJ, (2010) Coupled motions in enzyme catalysis. Curr Opin Chem Biol 14: 644-651.
8. Schwartz SD, Schramm VL, (2009) Enzymatic transition states and dynamic motion in barrier crossing. Nat Chem Biol 5: 551-558.
9. Adamczyk AJ, Cao J, Kamerlin SC, Warshel A, (2011) Catalysis by dihydrofolate reductase and other enzymes arises from electrostatic preorganization, not conformational motions. Proc Natl Acad Sci U S A 108: 14115-14120.
10. Kamerlin SC, Warshel A, (2010) At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis? Proteins 78: 1339-1375.
11. Agarwal PK, Billeter SR, Rajagopalan PT, Benkovic SJ, Hammes-Schiffer S, (2002) Network of coupled promoting motions in enzyme catalysis. Proc Natl Acad Sci U S A 99: 2794-2799.
12. Rod TH, Radkiewicz JL, Brooks CL 3rd, (2003) Correlated motion and the effect of distal mutations in dihydrofolate reductase. Proc Natl Acad Sci U S A 100: 6980-6985.
13. Cameron CE, Benkovic SJ, (1997) Evidence for a functional role of the dynamics of glycine-121 of Escherichia coli dihydrofolate reductase obtained from kinetic analysis of a site-directed mutant. Biochemistry 36: 15792-15800.
14. Wang L, Goodey NM, Benkovic SJ, Kohen A, (2006) Coordinated effects of distal mutations on environmentally coupled tunneling in dihydrofolate reductase. Proc Natl Acad Sci U S A 103: 15753-15758.
15. Li L, Falzone CJ, Wright PE, Benkovic SJ, (1992) Functional role of a mobile loop of Escherichia coli dihydrofolate reductase in transition-state stabilization. Biochemistry 31: 7826-7833.
16. Miller GP, Benkovic SJ, (1998) Strength of an interloop hydrogen bond determines the kinetic pathway in catalysis by Escherichia coli dihydrofolate reductase. Biochemistry 37: 6336-6342.
17. Miller GP, Wahnon DC, Benkovic SJ, (2001) Interloop contacts modulate ligand cycling during catalysis by Escherichia coli dihydrofolate reductase. Biochemistry 40: 867-875.
18. Watney JB, Agarwal PK, Hammes-Schiffer S, (2003) Effect of mutation on enzyme motion in dihydrofolate reductase. J Am Chem Soc 125: 3745-3750.
19. Gekko K, Kunori Y, Takeuchi H, Ichihara S, Kodama M, (1994) Point mutations at glycine-121 of Escherichia coli dihydrofolate reductase: important roles of a flexible loop in the stability and function. J Biochem 116: 34-41.
20. Thorpe IF, Brooks CL 3rd, (2004) The coupling of structural fluctuations to hydride transfer in dihydrofolate reductase. Proteins 57: 444-457.
21. Venkitakrishnan RP, Zaborowski E, McElheny D, Benkovic SJ, Dyson HJ, et al. (2004) Conformational changes in the active site loops of dihydrofolate reductase during the catalytic cycle. Biochemistry 43: 16046-16055.
22. Mauldin RV, Carroll MJ, Lee AL, (2009) Dynamic dysfunction in dihydrofolate reductase results from antifolate drug binding: modulation of dynamics within a structural state. Structure 17: 386-394.
23. Osborne MJ, Venkitakrishnan RP, Dyson HJ, Wright PE, (2003) Diagnostic chemical shift markers for loop conformation and substrate and cofactor binding in dihydrofolate reductase complexes. Protein Sci 12: 2230-2238.
24. Sawaya MR, Kraut J, (1997) Loop and subdomain movements in the mechanism of Escherichia coli dihydrofolate reductase: crystallographic evidence. Biochemistry 36: 586-603.
25. McElheny D, Schnell JR, Lansing JC, Dyson HJ, Wright PE, (2005) Defining the role of active-site loop fluctuations in dihydrofolate reductase catalysis. Proc Natl Acad Sci U S A 102: 5032-5037.
26. Loria JP, Rance M, Palmer AG, (1999) A relaxation-compensated Carr-Purcell-Meiboom-Gill sequence for characterizing chemical exchange by NMR spectroscopy. Journal of the American Chemical Society 121: 2331-2332.
27. Lipari G, Szabo A, (1982) Model-Free Approach to the Interpretation of Nuclear Magnetic-Resonance Relaxation in Macromolecules. 1. Theory and Range of Validity. Journal of the American Chemical Society 104: 4546-4559.
28. Lipari G, Szabo A, (1982) Model-Free Approach to the Interpretation of Nuclear Magnetic-Resonance Relaxation in Macromolecules. 2. Analysis of Experimental Results. Journal of the American Chemical Society 104: 4559-4570.
29. d'Auvergne EJ, Gooley PR, (2006) Model-free model elimination: A new step in the model-free dynamic analysis of NMR relaxation data. Journal of Biomolecular Nmr 35: 117-135.
30. Igumenova TI, Frederick KK, Wand AJ, (2006) Characterization of the fast dynamics of protein amino acid side chains using NMR relaxation in solution. Chemical Reviews 106: 1672-1699.
31. Muhandiram DR, Yamazaki T, Sykes BD, Kay LE, (1995) Measurement of H-2 T-1 and T-1p Relaxation-Times in Uniformly C-13-Labeled and Fractionally H-2-Labeled Proteins in Solution. Journal of the American Chemical Society 117: 11536-11544.
32. Millet O, Muhandiram DR, Skrynnikov NR, Kay LE, (2002) Deuterium spin probes of side-chain dynamics in proteins. 1. Measurement of five relaxation rates per deuteron in (13)C-labeled and fractionally (2)H-enriched proteins in solution. J Am Chem Soc 124: 6439-6448.
33. Mauldin RV, Lee AL, (2010) Nuclear magnetic resonance study of the role of M42 in the solution dynamics of Escherichia coli dihydrofolate reductase. Biochemistry 49: 1606-1615.
34. Clarkson MW, Lee AL, (2004) Long-range dynamic effects of point mutations propagate through side chains in the serine protease inhibitor eglin c. Biochemistry 43: 12448-12458.
35. Whitley MJ, Zhang J, Lee AL, (2008) Hydrophobic core mutations in CI2 globally perturb fast side-chain dynamics similarly without regard to position. Biochemistry 47: 8566-8576.
36. Sasso SP, Gilli RM, Sari JC, Rimet OS, Briand CM, (1994) Thermodynamic Study of Dihydrofolate-Reductase Inhibitor Selectivity. Biochimica Et Biophysica Acta-Protein Structure and Molecular Enzymology 1207: 74-79.
37. Bystroff C, Kraut J, (1991) Crystal structure of unliganded Escherichia coli dihydrofolate reductase. Ligand-induced conformational changes and cooperativity in binding. Biochemistry 30: 2227-2239.
38. Ohmae E, Iriyama K, Ichihara S, Gekko K, (1998) Nonadditive effects of double mutations at the flexible loops, glycine-67 and glycine-121, of Escherichia coli dihydrofolate reductase on its stability and function. J Biochem 123: 33-41.
39. Rajagopalan PT, Lutz S, Benkovic SJ, (2002) Coupling interactions of distal residues enhance dihydrofolate reductase catalysis: mutational effects on hydride transfer rates. Biochemistry 41: 12618-12628.
40. Clarkson MW, Gilmore SA, Edgell MH, Lee AL, (2006) Dynamic coupling and allosteric behavior in a nonallosteric protein. Biochemistry 45: 7693-7699.
41. Henzler-Wildman KA, Lei M, Thai V, Kerns SJ, Karplus M, et al. (2007) A hierarchy of timescales in protein dynamics is linked to enzyme catalysis. Nature 450: 913-916.
42. Boekelheide N, Salomon-Ferrer R, Miller TF 3rd, (2011) Dynamics and dissipation in enzyme catalysis. Proc Natl Acad Sci U S A 108: 16159-16163.
43. Sapienza PJ, Mauldin RV, Lee AL, (2010) Multi-timescale dynamics study of FKBP12 along the rapamycin-mTOR binding coordinate. J Mol Biol 405: 378-394.
44. Farrow NA, Muhandiram R, Singer AU, Pascal SM, Kay CM, et al. (1994) Backbone Dynamics of a Free and a Phosphopeptide-Complexed Src Homology-2 Domain Studied by N-15 Nmr Relaxation. Biochemistry 33: 5984-6003.
45. Lee LK, Rance M, Chazin WJ, Palmer AG, (1997) Rotational diffusion anisotropy of proteins from simultaneous analysis of N-15 and C-13(alpha) nuclear spin relaxation. Journal of Biomolecular Nmr 9: 287-298.
46. Osborne MJ, Wright PE, (2001) Anisotropic rotational diffusion in model-free analysis for a ternary DHFR complex. J Biomol NMR 19: 209-230.
47. Boyer JA, Lee AL, (2008) Monitoring aromatic picosecond to nanosecond dynamics in proteins via 13C relaxation: expanding perturbation mapping of the rigidifying core mutation, V54A, in eglin c. Biochemistry 47: 4876-4886.