Login Register Cart 0
Generic placeholder image

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Probing Protein-protein Interactions and Druggable Site Identification: Mechanistic Binding Events Between Ubiquitin and Zinc Finger with UFM1-specific Peptidase Domain Protein (ZUFSP)

Author(s): Mary B. Ajadi, Opeyemi S. Soremekun, Ahmed A Elrashedy, Fisayo A. Olotu, Hezekiel M. Kumalo and Mahmoud E.S. Soliman*

Volume 25, Issue 5, 2022

Published on: 03 February, 2021

Page: [831 - 837] Pages: 7

DOI: 10.2174/1386207324666210203175142

Price: $65

Abstract

Background: Deubiquitinating enzymes (DUBs) protein family have been implicated in some deregulated pathways involved in carcinogeneses, such as cell cycle, gene expression, and DNA damage response (DDR). Zinc finger with UFM1-specific peptidase domain protein (ZUFSP) is one of the recently discovered members of the DUBs.

Objectives: To identify and cross-validate the ZUFSP binding site using the bioinformatic tools, including SiteMap&Metapocket, respectively. To understand the molecular basis of complementary ZUFSP-Ub interaction and associated structural events using MD Simulation.

Methods: In this study, four binding pockets were predicted, characterized, and cross-validated based on physiochemical features such as site score, druggability score, site volume, and site size. Also, a molecular dynamics simulation technique was employed to determine the impact of ubiquitin-binding on ZUFSP.

Results: Site 1 with a site score 1.065, Size 102, D scores 1.00, and size volume 261 was predicted to be the most druggable site. Structural studies revealed that upon ubiquitin-binding, the motional movement of ZUFSP was reduced when compared to the unbound ZUFSP. Also, the ZUFSP helical arm (ZHA) domain orient in such a way that it moves closer to the Ub; this orientation enables the formation of a UBD which is very peculiar to ZUFSP.

Conclusion: The impact of ubiquitin on ZUFSP movement and the characterization of its predicted druggable site can be targeted in the development of therapeutics.

Keywords: Binding site, ZUFSP, ubiquitin, molecular dynamic simulation, deubiquitinating enzymes, cancer.

« Previous Next »
Graphical Abstract

[1]
Kulathu, Y.; Komander, D. Atypical ubiquitylation - the unexplored world of polyubiquitin beyond Lys48 and Lys63 linkages. Nat. Rev. Mol. Cell Biol., 2012, 13(8), 508-523.
[http://dx.doi.org/10.1038/nrm3394] [PMID: 22820888]
[2]
Kwasna, D.; Abdul Rehman, S.A.; Natarajan, J.; Matthews, S.; Madden, R.; De Cesare, V.; Weidlich, S.; Virdee, S.; Ahel, I.; Gibbs-Seymour, I.; Kulathu, Y. Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. Mol. Cell, 2018, 70(1), 150-164.e6.
[http://dx.doi.org/10.1016/j.molcel.2018.02.023] [PMID: 29576527]
[3]
Komander, D.; Rape, M. The ubiquitin code. Annu. Rev. Biochem., 2012, 81, 203-229.
[http://dx.doi.org/10.1146/annurev-biochem-060310-170328] [PMID: 22524316]
[4]
Abdul Rehman, S.A.; Kristariyanto, Y.A.; Choi, S-Y.; Nkosi, P.J.; Weidlich, S.; Labib, K.; Hofmann, K.; Kulathu, Y. MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes. Mol. Cell, 2016, 63(1), 146-155.
[http://dx.doi.org/10.1016/j.molcel.2016.05.009] [PMID: 27292798]
[5]
Clague, M.J.; Barsukov, I.; Coulson, J.M.; Liu, H.; Rigden, D.J.; Urbé, S. Deubiquitylases from genes to organism. Physiol. Rev., 2013, 93(3), 1289-1315.
[http://dx.doi.org/10.1152/physrev.00002.2013] [PMID: 23899565]
[6]
Mevissen, T.E.T.; Hospenthal, M.K.; Geurink, P.P.; Elliott, P.R.; Akutsu, M.; Arnaudo, N.; Ekkebus, R.; Kulathu, Y.; Wauer, T.; El Oualid, F.; Freund, S.M.; Ovaa, H.; Komander, D. OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell, 2013, 154(1), 169-184.
[http://dx.doi.org/10.1016/j.cell.2013.05.046] [PMID: 23827681]
[7]
Haahr, P.; Borgermann, N.; Guo, X.; Typas, D.; Achuthankutty, D.; Hoffmann, S.; Shearer, R.; Sixma, T.K.; Mailand, N. ZUFSP Deubiquitylates K63-Linked Polyubiquitin Chains to Promote Genome Stability. Mol. Cell, 2018, 70(1), 165-174.e6.
[http://dx.doi.org/10.1016/j.molcel.2018.02.024] [PMID: 29576528]
[8]
Hermanns, T.; Pichlo, C.; Woiwode, I.; Klopffleisch, K.; Witting, K.F.; Ovaa, H.; Baumann, U.; Hofmann, K. A family of unconventional deubiquitinases with modular chain specificity determinants. Nat. Commun., 2018, 9(1), 799.
[http://dx.doi.org/10.1038/s41467-018-03148-5] [PMID: 29476094]
[9]
Békés, M.; van der Heden van Noort, G.J.; Ekkebus, R.; Ovaa, H.; Huang, T.T.; Lima, C.D. Recognition of Lys48-linked di-ubiquitin and deubiquitinating activities of the SARS coronavirus papain-like protease. Mol. Cell, 2016, 62(4), 572-585.
[http://dx.doi.org/10.1016/j.molcel.2016.04.016] [PMID: 27203180]
[10]
Wertz, I.E.; Murray, J.M. Structurally-defined deubiquitinase inhibitors provide opportunities to investigate disease mechanisms. Drug Discov. Today. Technol., 2019, 31, 109-123.
[http://dx.doi.org/10.1016/j.ddtec.2019.02.003] [PMID: 31200854]
[11]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[12]
Case, D.A.; Cheatham, T.E., III; Darden, T.; Gohlke, H.; Luo, R.; Merz, K.M., Jr; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R.J. The Amber biomolecular simulation programs. J. Comput. Chem., 2005, 26(16), 1668-1688.
[http://dx.doi.org/10.1002/jcc.20290] [PMID: 16200636]
[13]
Shao, Y.; Molnar, L.F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S.T.; Gilbert, A.T.; Slipchenko, L.V.; Levchenko, S.V.; O’Neill, D.P.; DiStasio, R.A., Jr; Lochan, R.C.; Wang, T.; Beran, G.J.; Besley, N.A.; Herbert, J.M.; Lin, C.Y.; Van Voorhis, T.; Chien, S.H.; Sodt, A.; Steele, R.P.; Rassolov, V.A.; Maslen, P.E.; Korambath, P.P.; Adamson, R.D.; Austin, B.; Baker, J.; Byrd, E.F.; Dachsel, H.; Doerksen, R.J.; Dreuw, A.; Dunietz, B.D.; Dutoi, A.D.; Furlani, T.R.; Gwaltney, S.R.; Heyden, A.; Hirata, S.; Hsu, C.P.; Kedziora, G.; Khalliulin, R.Z.; Klunzinger, P.; Lee, A.M.; Lee, M.S.; Liang, W.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E.I.; Pieniazek, P.A.; Rhee, Y.M.; Ritchie, J.; Rosta, E.; Sherrill, C.D.; Simmonett, A.C.; Subotnik, J.E.; Woodcock, H.L., III; Zhang, W.; Bell, A.T.; Chakraborty, A.K.; Chipman, D.M.; Keil, F.J.; Warshel, A.; Hehre, W.J.; Schaefer, H.F., III; Kong, J.; Krylov, A.I.; Gill, P.M.; Head-Gordon, M. Advances in methods and algorithms in a modern quantum chemistry program package. Phys. Chem. Chem. Phys., 2006, 8(27), 3172-3191.
[http://dx.doi.org/10.1039/B517914A] [PMID: 16902710]
[14]
El Rashedy, A.A.; Olotu, F.A.; Soliman, M.E.S. Dual drug targeting of mutant Bcr-Abl induces inactive conformation: New strategy for the treatment of chronic myeloid leukemia and overcoming monotherapy resistance. Chem. Biodivers., 2018, 15(3), e1700533.
[http://dx.doi.org/10.1002/cbdv.201700533] [PMID: 29325229]
[15]
Joy, M.; Elrashedy, A.A.; Mathew, B. Discovery of new class of methoxy carrying isoxazole derivatives as COX-II inhibitors: Investigation of a detailed molecular dynamics study. J. Mol. Struct., 2018, 1157, 19-28.
[http://dx.doi.org/10.1016/j.molstruc.2017.11.109]
[16]
Metwally, K.; Pratsinis, H.; Kletsas, D.; Quattrini, L.; Coviello, V.; Motta, C.; El-Rashedy, A.A.; Soliman, M.E. Novel quinazolinone-based 2,4-thiazolidinedione-3-acetic acid derivatives as potent aldose reductase inhibitors. Future Med. Chem., 2017, 9(18), 2147-2166.
[http://dx.doi.org/10.4155/fmc-2017-0149] [PMID: 29098865]
[17]
Soremekun, O.S.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. Recruiting monomer for dimer formation: resolving the antagonistic mechanisms of novel immune check point inhibitors against Programmed Death Ligand-1 in cancer immunotherapy. Mol. Simul., 2019.
[http://dx.doi.org/10.1080/08927022.2019.1593977]
[18]
Soremekun, O.S.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. Drug promiscuity: Exploring the polypharmacology potential of 1, 3, 6-trisubstituted 1, 4-diazepane-7-ones as an inhibitor of the ‘god father’ of immune checkpoint. Comput. Biol. Chem., 2019, 80, 433-440.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.05.009] [PMID: 31146119]
[19]
Yang, Y.; Liu, H.; Yao, X. Understanding the molecular basis of MK2-p38α signaling complex assembly: insights into protein-protein interaction by molecular dynamics and free energy studies. Mol. Biosyst., 2012, 8(8), 2106-2118.
[http://dx.doi.org/10.1039/c2mb25042j] [PMID: 22648002]
[20]
Roche, D.B.; Brackenridge, D.A.; McGuffin, L.J. Proteins and their interacting partners: An introduction to protein-ligand binding site prediction methods. Int. J. Mol. Sci., 2015, 16(12), 29829-29842.
[http://dx.doi.org/10.3390/ijms161226202] [PMID: 26694353]
[21]
Friesner, RA; Banks, JL; Murphy, RB Glide A New Approach for Rapid, Accurate Docking.pdf, , 1739-1749.
[http://dx.doi.org/10.1021/jm0306430]
[22]
Hsu, F-S; Su, C-H; Huang, K-H A Comprehensive Review of US FDA-Approved Immune Checkpoint Inhibitors in Urothelial Carcinoma., 2017.
[http://dx.doi.org/10.1155/2017/6940546]
[23]
Pitera, J.W. Expected distributions of root-mean-square positional deviations in proteins. J. Phys. Chem. B, 2014, 118(24), 6526-6530.
[http://dx.doi.org/10.1021/jp412776d] [PMID: 24655018]
[24]
Fuglebakk, E.; Echave, J.; Reuter, N. Measuring and comparing structural fluctuation patterns in large protein datasets. Bioinformatics, 2012, 28(19), 2431-2440.
[http://dx.doi.org/10.1093/bioinformatics/bts445] [PMID: 22796957]
[25]
Lobanov, M.Y.; Bogatyreva, N.S.; Galzitskaya, O.V. Radius of gyration as an indicator of protein structure compactness. Mol. Biol., 2008.
[http://dx.doi.org/10.1134/S0026893308040195] [PMID: 18856071]
[26]
Lins, L.; Thomas, A.; Brasseur, R. Analysis of accessible surface of residues in proteins. Protein Sci., 2003, 12(7), 1406-1417.
[http://dx.doi.org/10.1110/ps.0304803] [PMID: 12824487]

Rights & Permissions Print Cite
Article Metrics
18
1
© 2024 Bentham Science Publishers | Privacy Policy