Homology Modeling and Virtual Screening of Proteins Related to PXE and PXE-like Diseases: Insights for Overlapping Metabolites

Author(s): Jannatul Naima, Ruhshan A. Abir, Mohammad J. Hosen*

Journal Name: Current Pharmaceutical Biotechnology

Volume 21 , Issue 14 , 2020


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Graphical Abstract:


Abstract:

Background: The molecular etiology of Pseudoxanthoma Elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in the ABCC6, but also in ENPP1 and GGCX, can cause resembling phenotypes.

Methods: To get insights on the common pathway, the overlapping metabolites for these three proteins were predicted through 3D homology modeling and virtual screening. 3D homology models of ABCC6, ENPP1, and GGCX were generated by the MODELLER program, which were further validated using RAMPAGE and ERRAT servers. Substrate binding sites of ABCC6 were predicted using blind docking of reported in vitro substrates.

Results: Virtual screening against the substrate binding site of ABCC6 using metabolites listed in Human Metabolome Databases (HMDB) revealed the best possible substrate of ABCC6. Those listed metabolites were further docked against predicted substrate binding sites of GGCX and ENPP1. Molecular docking and virtual screening revealed a list of 133 overlapping metabolites of these three proteins. Most of them are Phosphatidylinositol (PI), Phosphatidylserine (PS), Diacylglycerol (DAG), phosphatidic acid, oleanolic acid metabolites and were found to have links with calcification.

Conclusion: These predicted overlapping metabolites may give novel insights for searching common pathomechanism for PXE and PXE-like diseases.

Keywords: PXE, ABCC6, ENPP1, GGCX, Homology modeling, molecular docking, soft-tissue-calcification.

[1]
Jiang, Q.; Endo, M.; Dibra, F.; Wang, K.; Uitto, J. Pseudoxanthoma elasticum is a metabolic disease. J. Invest. Dermatol., 2009, 129(2), 348-354.
[http://dx.doi.org/10.1038/jid.2008.212] [PMID: 18685618]
[2]
Uitto, J.; Jiang, Q.; Váradi, A.; Bercovitch, L.G.; Terry, S.F. Pseudoxanthoma elasticum: Diagnostic features, classification, and treatment options. Expert Opin. Orphan Drugs, 2014, 2(6), 567-577.
[http://dx.doi.org/10.1517/21678707.2014.908702] [PMID: 25383264]
[3]
Ringpfeil, F.; Lebwohl, M.G.; Christiano, A.M.; Uitto, J. Pseudoxanthoma elasticum: Mutations in the MRP6 gene encoding a transmembrane ATP-Binding Cassette (ABC) transporter. Proc. Natl. Acad. Sci. USA, 2000, 97(11), 6001-6006.
[http://dx.doi.org/10.1073/pnas.100041297] [PMID: 10811882]
[4]
Nitschke, Y.; Baujat, G.; Botschen, U.; Wittkampf, T.; du Moulin, M.; Stella, J.; Le Merrer, M.; Guest, G.; Lambot, K.; Tazarourte-Pinturier, M.F.; Chassaing, N.; Roche, O.; Feenstra, I.; Loechner, K.; Deshpande, C.; Garber, S.J.; Chikarmane, R.; Steinmann, B.; Shahinyan, T.; Martorell, L.; Davies, J.; Smith, W.E.; Kahler, S.G.; McCulloch, M.; Wraige, E.; Loidi, L.; Höhne, W.; Martin, L.; Hadj-Rabia, S.; Terkeltaub, R.; Rutsch, F. Generalized arterial calcification of infancy and Pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6. Am. J. Hum. Genet., 2012, 90(1), 25-39.
[http://dx.doi.org/10.1016/j.ajhg.2011.11.020] [PMID: 22209248]
[5]
Rutsch, F.; Böyer, P.; Nitschke, Y.; Ruf, N.; Lorenz-Depierieux, B.; Wittkampf, T.; Weissen-Plenz, G.; Fischer, R.J.; Mughal, Z.; Gregory, J.W.; Davies, J.H.; Loirat, C.; Strom, T.M.; Schnabel, D.; Nürnberg, P.; Terkeltaub, R. GACI Study Group. Hypophosphatemia, hyperphosphaturia, and bisphosphonate treatment are associated with survival beyond infancy in generalized arterial calcification of infancy. Circ Cardiovasc Genet, 2008, 1(2), 133-140.
[http://dx.doi.org/10.1161/CIRCGENETICS.108.797704] [PMID: 20016754]
[6]
Li, Q.; Grange, D.K.; Armstrong, N.L.; Whelan, A.J.; Hurley, M.Y.; Rishavy, M.A.; Hallgren, K.W.; Berkner, K.L.; Schurgers, L.J.; Jiang, Q.; Uitto, J. Mutations in the GGCX and ABCC6 genes in a family with Pseudoxanthoma elasticum-like phenotypes. J. Invest. Dermatol., 2009, 129(3), 553-563.
[http://dx.doi.org/10.1038/jid.2008.271] [PMID: 18800149]
[7]
Li, Q.; Brodsky, J.L.; Conlin, L. Bradfield, J.; Pawel, B.; Glatz, A.; Schurgers, L.J.; Deardoff, M.A.; Levine, M.; Uitto, J. Mutations in the ABCC6 gene can cause generalized arterial calcification of infancy in addition to Pseudoxanthoma elasticum. J. Invest. Dermatol., 2012, 132, S91.
[8]
Vanakker, OM.; Leroy, BP.; Schurgers, LJ.; Vermeer, C.; Coucke, PJ.; De Paepe, A. Atypical presentation of Pseudoxanthoma elasticum with abdominal cutis laxa: Evidence for a spectrum of ectopic calcification disorders? Am. J. Med. Genet. A, 2011, 155(A), 2855-2859.
[http://dx.doi.org/10.1002/ajmg.a.34264]
[9]
Gusdorf, L.; Mitcov, M.; Maradeix, S.; Cunat, S.; Martin, L.; Cribier, B. Pseudoxanthoma elasticum -like disease with deficiency of vitamin K-dependent clotting factors and cutis laxa features. Ann. Dermatol. Venereol., 2016, 143(4), 279-283.
[http://dx.doi.org/10.1016/j.annder.2015.11.010] [PMID: 26944767]
[10]
Hosen, M.J.; Zubaer, A.; Thapa, S.; Khadka, B.; De Paepe, A.; Vanakker, O.M. Molecular docking simulations provide insights in the substrate binding sites and possible substrates of the ABCC6 transporter. PLoS One, 2014, 9(7)e102779
[http://dx.doi.org/10.1371/journal.pone.0102779] [PMID: 25062064]
[11]
Roy, A.; Kucukural, A.; Zhang, Y. I-TASSER: A unified platform for automated protein structure and function prediction. Nat. Protoc., 2010, 5(4), 725-738.
[http://dx.doi.org/10.1038/nprot.2010.5] [PMID: 20360767]
[12]
Kurowski, M.A.; Bujnicki, J.M. GeneSilico protein structure prediction meta-server. Nucleic Acids Res., 2003, 31(13), 3305-3307.
[http://dx.doi.org/10.1093/nar/gkg557] [PMID: 12824313]
[13]
Wallner, B.; Elofsson, A. Pcons5: Combining consensus, structural evaluation and fold recognition scores. Bioinformatics, 2005, 21(23), 4248-4254.
[http://dx.doi.org/10.1093/bioinformatics/bti702] [PMID: 16204344]
[14]
Fiser, A.; Sali, A. Modeller: Generation and refinement of homology-based protein structure models. Methods Enzymol., 2003, 374, 461-491.
[http://dx.doi.org/10.1016/S0076-6879(03)74020-8] [PMID: 14696385]
[15]
Krieger, E.; Joo, K.; Lee, J.; Lee, J.; Raman, S.; Thompson, J.; Tyka, M.; Baker, D.; Karplus, K. Improving physical realism, stereochemistry, and side-chain accuracy in homology modeling: Four approaches that performed well in CASP8. Proteins, 2009, 77(Suppl. 9), 114-122.
[http://dx.doi.org/10.1002/prot.22570] [PMID: 19768677]
[16]
Krogh, A.; Larsson, B.; von Heijne, G.; Sonnhammer, E.L. Predicting transmembrane protein topology with a hidden Markov model: Application to complete genomes. J. Mol. Biol., 2001, 305(3), 567-580.
[http://dx.doi.org/10.1006/jmbi.2000.4315] [PMID: 11152613]
[17]
Kozlowski, L.P.; Bujnicki, J.M. MetaDisorder: A meta-server for the prediction of intrinsic disorder in proteins. BMC Bioinformatics, 2012, 13, 111.
[http://dx.doi.org/10.1186/1471-2105-13-111] [PMID: 22624656]
[18]
Colovos, C.; Yeates, T.O. Verification of protein structures: Patterns of nonbonded atomic interactions. Protein Sci., 1993, 2(9), 1511-1519.
[http://dx.doi.org/10.1002/pro.5560020916] [PMID: 8401235]
[19]
Lovell, S.C.; Davis, I.W.; Arendall, W.B., III; de Bakker, P.I.W.; Word, J.M.; Prisant, M.G.; Richardson, J.S.; Richardson, D.C. Structure validation by Calpha geometry: Phi, psi and Cbeta deviation. Proteins, 2003, 50(3), 437-450.
[http://dx.doi.org/10.1002/prot.10286] [PMID: 12557186]
[20]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[21]
Trott, O.; Olson, A.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[22]
Jansen, R.S.; Duijst, S.; Mahakena, S.; Sommer, D.; Szeri, F.; Váradi, A.; Plomp, A.; Bergen, A.A.; Oude Elferink, R.P.; Borst, P.; van de Wetering, K. ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler. Thromb. Vasc. Biol., 2014, 34(9), 1985-1989.
[http://dx.doi.org/10.1161/ATVBAHA.114.304017] [PMID: 24969777]
[23]
Vanakker, O.M.; Martin, L.; Gheduzzi, D.; Leroy, B.P.; Loeys, B.L.; Guerci, V.I.; Matthys, D.; Terry, S.F.; Coucke, P.J.; Pasquali-Ronchetti, I.; De Paepe, A. Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J. Invest. Dermatol., 2007, 127(3), 581-587.
[http://dx.doi.org/10.1038/sj.jid.5700610] [PMID: 17110937]
[24]
Kariminejad, A.; Bozorgmehr, B.; Najafi, A.; Khoshaeen, A.; Ghalandari, M.; Najmabadi, H.; Kariminejad, M.H.; Vanakker, O.M.; Hosen, M.J.; Malfait, F.; Quaglino, D.; Florijn, R.J.; Bergen, A.A.B.; Hennekam, R.C. Retinitis pigmentosa, cutis laxa, and Pseudoxanthoma elasticum-like skin manifestations associated with GGCX mutations. J. Invest. Dermatol., 2014, 134(9), 2331-2338.
[http://dx.doi.org/10.1038/jid.2014.191] [PMID: 24739904]
[25]
Cecil, D.L.; Terkeltaub, R.A. Arterial calcification is driven by RAGE in Enpp1-/- mice. J. Vasc. Res., 2011, 48(3), 227-235.
[http://dx.doi.org/10.1159/000318805] [PMID: 21099228]
[26]
Hosen, M.J.; Lamoen, A.; De Paepe, A.; Vanakker, O.M. Histopathology of Pseudoxanthoma elasticum and related disorders: Histological hallmarks and diagnostic clues. Scientifica (Cairo), 2012, 2012598262
[http://dx.doi.org/10.6064/2012/598262] [PMID: 24278718]
[27]
Hosen, M.J.; Coucke, P.J.; Le Saux, O.; De Paepe, A.; Vanakker, O.M. Perturbation of specific pro-mineralizing signalling pathways in human and murine Pseudoxanthoma elasticum. Orphanet J. Rare Dis., 2014, 9, 66.
[http://dx.doi.org/10.1186/1750-1172-9-66] [PMID: 24775865]
[28]
Li, Q.; Jiang, Q.; Schurgers, L.J.; Uitto, J. Pseudoxanthoma elasticum: Reduced gamma-glutamyl carboxylation of matrix gla protein in a mouse model (Abcc6-/-). Biochem. Biophys. Res. Commun., 2007, 364(2), 208-213.
[http://dx.doi.org/10.1016/j.bbrc.2007.09.122] [PMID: 17942075]


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VOLUME: 21
ISSUE: 14
Year: 2020
Page: [1470 - 1478]
Pages: 9
DOI: 10.2174/1389201021666200519115032
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