In silicoAnalysis of the Structural Properties of PSMA and its Energetic Relationship with Zn as Cofactor

M. A.  Fuentes; L. A.  Mandujano; R.  Lopez; L. R.  Guarneros; E.  Azorin; D.  Osorio-Gonzalez

doi:10.15415/jnp.2018.61020

Authors

M. A. Fuentes Molecular Biophysics Laboratory of the Faculty of Sciences, Autonomous University of Mexico State, Mexico
L. A. Mandujano Molecular Biophysical Modeling and Design Laboratory, Mexiquense University, S. C.
R. Lopez Multiscale Molecular Bioengineering Laboratory of the Faculty of Sciences, Autonomous University of Mexico State, Mexico
L. R. Guarneros Multiscale Molecular Bioengineering Laboratory of the Faculty of Sciences, Autonomous University of Mexico State, Mexico
E. Azorin Multiscale Molecular Bioengineering Laboratory of the Faculty of Sciences, Autonomous University of Mexico State, Mexico
D. Osorio-Gonzalez Molecular Biophysics Laboratory of the Faculty of Sciences, Autonomous University of Mexico State, Mexico

DOI:

https://doi.org/10.15415/jnp.2018.61020

Keywords:

PSMA structural analysis, PSMA with and without Zn as cofactor

Abstract

The prostate-specific membrane antigen (PSMA) is a 100 kDa type II transmembrane glycoprotein with enzymatic activity similar to the family of zinc-dependent exopeptidases. This protein is of great medical and pharmacological interest as overexpression in prostate cells is related to the progression of prostate cancer; therefore, it represents an important target for the design of radiopharmaceuticals. The presence of two Zn²⁺ ions in the active site is crucial to the enzymatic activity and the design of high-affinity inhibitors. The amino acid residues coordinating these ions are highly conserved in PSMA orthologs from plants to mammals, and site-mutagenesis assays of these residues show a loss of enzymatic function or reduction of the kinetic parameters. In the present work, we performed molecular dynamics simulation of PSMA with the purpose of characterizing it energetically and structurally. We elucidated the differences of PSMA with its two Zn⁺² ions as cofactors and without them in the free energy profile, and in four structural parameters: root mean square deviations and root mean square fluctuations by atom and amino acid residue, radius of gyration, and solvent accessible surface area.

Downloads

Download data is not yet available.

References

M. Ervik, F. Lam, J. Ferlay, L. Mery, I. Soerjomataram, F. Bray, Lyon, France: International Agency for Research on Cancer. Cancer Today(2016). http://gco.iarc.fr/today. Accessed 10 April 2018.

R. Carter, A. Feldman, J. Coyle, Proceedings of The National Academy of Scienc0es, 93(2), 749–753 (1996). https://doi.org/10.1073/pnas.93.2.749

M. N. Pangalos J. M. Neefs, M. Somers, P. Verhasselt, M. Bekkers, L. van der Helm et al., Journal of Biological Chemistry, 274(13), 8470–8483 (1999). https://doi.org/10.1074/jbc.274.13.8470

J. T. Pinto, B. P. Suffoletto, T. M. Berzin, C. H. Qiao, S. Lin, W. P. Tong et al., Clinical Cancer Research, 2(9), 1445–1451 (1996).

R. Lapidus, C. Tiffany, J. Isaacs, B. Slusher, The Prostate, 45(4), 350–354 (2000). https://doi.org/10.1002/1097-0045(20001201)45:4<350::AIDPROS10>3.0.CO;2-U

J. Troyer, M. Beckett, G. Wright, International Journal of Cancer, 62(5), 552–558 (1995). https://doi.org/10.1002/ijc.2910620511

A. P. Kiess, S. R. Banerjee, R. C. Mease, S. P. Rowe, A. Rao, C. A. Foss et al., European Journal of Nuclear Medicine and Molecular Imaging, 59(3), 241 (2015).

S. Lütje, S. Heskamp, A. S. Cornelissen, T. D. Poeppel, S. A. van den Broek, S. Rosenbaum-Krumme et al., Theranostics, 5(12), 1388 (2015). https://doi.org/10.7150/thno.13348

K. P. Maresca, S. M. Hillier, F. J. Femia, D. Keith, C. Barone, J. L. Joyal et al., Journal of Medicinal Chemistry, 52(2), 347–357 (2008). https://doi.org/10.1021/jm800994j

Z. Zhang, Z. Zhu, D. Yang, W. Fan, J. Wang, X. Li et al., Oncology letters, 12(2), 1001–1006 (2016). https://doi.org/10.3892/ol.2016.4699

A. Escudero-Castellanos, B. E. Ocampo-García, G. Ferro-Flores, K. Isaac-Olivé, C. L. Santos-Cuevas, A. Olmos-Ortiz et al., Journal of Radioanalytical and Nuclear Chemistry, 314(3), 2201–2207 (2017). https://doi.org/10.1007/s10967-017-5555-9

W. P. Fendler, K. Rahbar, K. Herrmann, C. Kratochwil and M. Eiber, Journal of Nuclear Medicine, 58(8), 1196–1200 (2017). https://doi.org/10.2967/jnumed.117.191023

C. Kratochwil, F. Bruchertseifer, F. L. Giesel, M. Weis, F. A. Verburg, F. Mottaghy et al., Journal of Nuclear Medicine, 57(12), 1941–1944 (2016). https://doi.org/10.2967/jnumed.116.178673

C. M. Zechmann, A. Afshar-Oromieh, T. Armor, J. B. Stubbs, W. Mier, B. Hadaschik et al., European Journal of Nuclear Medicine and Molecular Imaging, 41(7), 1280–1292 (2014). https://doi.org/10.1007/s00259-014-2713-y

M. Benešová, M. Schäfer, U. Bauder-Wüst, A. AfsharOromieh, C. Kratochwil, W. Mier et al., Journal of Nuclear Medicine, 56(6), 914–920 (2015). https://doi.org/10.2967/jnumed.114.147413

C. Kratochwil, F. L. Giesel, M. Eder, A. AfsharOromieh, M. Benesová, W. Mier et al., European Journal of Nuclear Medicine and Molecular Imaging, 42(6), 987 (2015). https://doi.org/10.1007/s00259-014-2978-1

M. I. Davis, M. J. Bennett, L. M. Thomas, P. J. Bjorkman, Proceedings of the National Academy of Sciences, 102(17), 5981–5986 (2005). https://doi.org/10.1073/pnas.0502101102

J. R. Mesters, C. Barinka, W. Li, T. Tsukamoto, P. Majer, B. S. Slusher et al., The EMBO journal, 25(6), 1375–1384 (2006). https://doi.org/10.1038/sj.emboj.7600969

J. Pavlicek, J. Ptacek, C. Barinka, Current Medicinal Chemistry, 19(9), 1300–1309 (2012). https://doi.org/10.2174/092986712799462667

S. R. Banerjee, C. A. Foss, M. Castanares, R. C. Mease, Y. Byun, J. J. Fox et al., Journal of Medicinal Chemistry, 51(15), 4504–4517 (2008). https://doi.org/10.1021/jm800111u

S. M. Hillier, K. P. Maresca, F. J. Femia, J. C. Marquis, C. A. Foss, N. Nguyen et al. Cancer Research, 69(17), 6932–6940 (2009). https://doi.org/10.1158/0008-5472.CAN-09-1682

P. Mlčochová, A. Plechanovova, C. Bařinka, D. Mahadevan, J. W. Saldanha, L. Rulíšek, J. Konvalinka, The FEBS Journal, 274(18), 4731–4741 (2007). https://doi.org/10.1111/j.1742-4658.2007.06021.x

C. Barinka, Y. Byun, C. L. Dusich, S. R. Banerjee, Y. Chen, M. Castanares et al., Journal of Medicinal Chemistry, 51(24), 7737–7743 (2008). https://doi.org/10.1021/jm800765e

D. Ferraris, K. Shukla, T. Tsukamoto, Current Medicinal Chemistry, 19(9), 1282–1294 (2012). https://doi.org/10.2174/092986712799462658

H. S. Speno, R. Luthi-Carter, W. L. Macias, S. L. Valentine, A. R. Joshi, J. T. Coyle, Moeluclar Pharmacology, 55(1), 179–185 (1999).