Zika virus proteins at an atomic scale: how does structural biology help us to understand and develop vaccines and drugs against Zika virus infection?

Valente, Ana Paula; Moraes, Adolfo Henrique

doi:10.1590/1678-9199-JVATITD-2019-0013

Ana Paula Valente

National Center of Magnetic Resonance, Leopoldo de Meis Institute of Medical Biochemistry, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil.

Adolfo Henrique Moraes

Department of Chemistry, Institute of Exact Sciences, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil.

https://orcid.org/0000-0002-3344-4084

*
Correspondence
: adolfo.dq.ufmg@gmail.com

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

APV reviewed the literature and contributed in writing the manuscript. AHM reviewed the literature and was the major contributor in writing the manuscript. All authors read and approved the final manuscript.

Figures (4)
Tables (1)

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Figure 1.
(A) CryoEM structure of ZIKV (PDB ID: 5IZ7) and DENV4 (PDB ID: 4CBF). (B) Model of protein E and protein M based on Cryo-EM density maps (PDB ID: 5IZ7). (C) Schematic domain organization of the ectodomain of ZIKV protein E. (D) Structure of ZIKV protein E dimer (PDB ID: 5JHM) and its three domains. (E) Structure of ZIKV-antibody complex (PDB ID: 5LCV).

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Figure 2.
(A) Domain organization of NS1. Glycosylated residues R130 and R205 are identified by hexagons. (B) X-ray crystal structure of ZIKV NS1 dimmer (PDB ID:5GS6). ZIKV domains are colored following the color pattern of panel A.

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Figure 3.
(A) Schematic domain organization of ZIKV NS3. (B), (C) Unlinked NS2B-NS3 protease complex (bZipPro) in close conformation (PDB ID: 5GPI) and NS2B-NS3 protease complex (eZipPro) after cleavage also in close conformation (PDB ID: 5GJ4), respectively. Side chains of catalytic residues H51, D75 and S135 are colored in magenta. (C) The processed tetrapeptide TGKR from the linker region is colored in orange. (D) Subdomain organization of NS3 helicase (PDB ID: 5JMT). (E) Superposition of crystal structures of NS3 helicase free (grey) (PDB ID: 5JMT) and complexed with single-chain RNA fragment (AGAUC) (green) (PDB ID: 5GJB). (F) Crystal structure of NS2B-NS3 protease-dipeptide inhibitor complex (PDB ID: 5MRK). (G) ¹H-¹⁵N HSQC spectra of NS2B-NS3 protease bZiPro in the absence and presence of dipeptide inhibitor AcKR-H and structure of the bZiPro- AcKR-H complex adapted from [5656.Li Y, Zhang Z, Phoo WW, Loh YR, Wang W, Liu S, et al. Structural dynamics of Zika virus NS2B-NS3 protease binding to dipeptide inhibitors. Structure. 2017;25(8):1242-50.].

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Figure 4.
(A) Schematic domain organization of ZIKV NS5. (B) Structure of ZIKV NS5 (PDB ID: 5FTR). (C) Superposition of NS5 structures of DENV3 (PDB ID: 5CCV) and ZIKV (PDB ID: 5FTR). (D) Superposition of NS5 structures of JEV (PDB ID: 4K6M) and ZIKV (PDB ID: 5FTR). (E) Structure of NS5 Mtase complexed with SAM-analogue inhibitor sinefungin (PDB ID: 5MRK).

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Table 1.
Structural information on Zika virus proteins

Protein	PDB	Ligand	Reference
Glycoprotein E	5KVE-DIII	ZV-48 Antibody scFv	[88.Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, et al. Structural basis of Zika virus-specific antibody protection. Cell. 2016;166(4):1016-27.]
	5KVD-DIII	ZV-2 Antibody Fab	[88.Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, et al. Structural basis of Zika virus-specific antibody protection. Cell. 2016;166(4):1016-27.]
	5KVF-DIII	ZV-64 Antibody Fab	[88.Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, et al. Structural basis of Zika virus-specific antibody protection. Cell. 2016;166(4):1016-27.]
	5KVG-DIII	ZV-67 Antibody Fab	[88.Zhao H, Fernandez E, Dowd KA, Speer SD, Platt DJ, Gorman MJ, et al. Structural basis of Zika virus-specific antibody protection. Cell. 2016;166(4):1016-27.]
	5LBS	Human antibody EDE1 C8 - scfv	[99.Barba-Spaeth G, Dejnirattisai W, Rouvinski A, Vaney MC, Medits I, Sharma A, et al. Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature. 2016;536(7614):48-53.]
	5LBV	-	[99.Barba-Spaeth G, Dejnirattisai W, Rouvinski A, Vaney MC, Medits I, Sharma A, et al. Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature. 2016;536(7614):48-53.]
	5LCV	Human antibody EDE2 A11-FAB	[99.Barba-Spaeth G, Dejnirattisai W, Rouvinski A, Vaney MC, Medits I, Sharma A, et al. Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature. 2016;536(7614):48-53.]
	5JHL	FAB	[1010.Dai L, Song J, Lu X, Deng YQ, Musyoki AM, Cheng H, et al. Structures of the Zika virus envelope protein and Its complex with a flavivirus broadly protective antibody. Cell Host Microbe. 2016;19(5):696-704.]
	5JHM	-	[1010.Dai L, Song J, Lu X, Deng YQ, Musyoki AM, Cheng H, et al. Structures of the Zika virus envelope protein and Its complex with a flavivirus broadly protective antibody. Cell Host Microbe. 2016;19(5):696-704.]
NS3 helicase	5JWH	-	[1111.Cao X, Li Y, Jin X, Li Y, Guo F, Jin T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res. 2016;44(21):10505-14.]
	5K8I	ATP	[1111.Cao X, Li Y, Jin X, Li Y, Guo F, Jin T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res. 2016;44(21):10505-14.]
	5K8L	GSP	[1111.Cao X, Li Y, Jin X, Li Y, Guo F, Jin T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res. 2016;44(21):10505-14.]
	5K8T	GSP, Mg²⁺	[1111.Cao X, Li Y, Jin X, Li Y, Guo F, Jin T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res. 2016;44(21):10505-14.]
	5K8U	ADP, Mn²⁺	[1111.Cao X, Li Y, Jin X, Li Y, Guo F, Jin T. Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design. Nucleic Acids Res. 2016;44(21):10505-14.]
	5GJB	ss-RNA	[1212.Tian H, Ji X, Yang X, Zhang Z, Lu Z, Yang K, et al. Structural basis of Zika virus helicase in recognizing its substrates. Protein Cell. 2016;7(8):562-70.]
	5GJC	ATP, Mn²⁺	[1212.Tian H, Ji X, Yang X, Zhang Z, Lu Z, Yang K, et al. Structural basis of Zika virus helicase in recognizing its substrates. Protein Cell. 2016;7(8):562-70.]
	5JRC	-	[1313.Jain R, Coloma J, Garcia-Sastre A, Aggarwal AK. Structure of the NS3 helicase from Zika virus. Nat Struct Mol Biol. 2016;23(8):752-4.]
	5JMT	-	[1414.Tian H, Ji X, Yang X, Xie W, Yang K, Chen C, et al. The crystal structure of Zika virus helicase: basis for antiviral drug design. Protein Cell. 2016;7(6):450-4.]
NS2B-NS3 serine protease	5GJ4	Last four amino acids of NS2B cofactor	[1515.Phoo WW, Li Y, Zhang Z, Lee MY, Loh YR, Tan YB, et al. Structure of the NS2B-NS3 protease from Zika virus after self-cleavage. Nat Commun. 2016;7:13410.]
	5T1V	-
	5LCO	Boronate inhibitor	[1616.Lei J, Hansen G, Nitsche C, Klein CD, Zhang L, Hilgenfeld R. Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science. 2016;353(6298):503-5.]
NS5 methyltransferase	5TFR	2 Zn²⁺	[1717.Zhang C, Feng T, Cheng J, Li YY, Yin X, Zeng W, et al. Structure of the NS5 methyltransferase from Zika virus and implications in inhibitor design. Biochem Biophys Res Commun. 2016;492(4):624-30.]
	5TMH	2 Zn²⁺, S-adenosyl-L-homocysteine
	5U0B	2 Zn²⁺, S-adenosyl-L-homocysteine	[1818.Zhao B, Yi G, Du F, Chuang YCY-C, Vaughan RCRC, Sankaran B, et al. Structure and function of the Zika virus full-length NS5 protein. Nat Commun. 2017;8:14762.]
	5U0C	2 Zn²⁺	[1818.Zhao B, Yi G, Du F, Chuang YCY-C, Vaughan RCRC, Sankaran B, et al. Structure and function of the Zika virus full-length NS5 protein. Nat Commun. 2017;8:14762.]
	5KQR (MTase)	S-adenosylmethionine	[1919.Coloma J, Jain R, Rajashankar KRR, García-Sastre A, Aggarwal AKK. Structures of NS5 methyltransferase from Zika virus. Cell Rep. 2016;16(12):3097-102.]
	5KQS (MTase)	S-adenosylmethionine,7-methyl-guanosine-5'-diphosphate	[1919.Coloma J, Jain R, Rajashankar KRR, García-Sastre A, Aggarwal AKK. Structures of NS5 methyltransferase from Zika virus. Cell Rep. 2016;16(12):3097-102.]
NS1	5K6K	-	[2020.Brown WC, Akey DL, Konwerski JR, Tarrasch JT, Skiniotis G, Kuhn RJ, et al. Extended surface for membrane association in Zika virus NS1 structure. Nat Struct Mol Biol. 2016;23(9):1-4.]
	5IY3	-	[2121.Song H, Qi J, Haywood J, Shi Y, Gao GF. Zika virus NS1 structure reveals diversity of electrostatic surfaces among flaviviruses. Nat Struct Mol Biol. 2016;23(5):1-4.]
	5GS6	-	[2222.Xu X, Song H, Qi J, Liu Y, Wang H, Su C, et al. Contribution of intertwined loop to membrane association revealed by Zika virus full-length NS1 structure. EMBO J. 2016;35(20):2170-8.]

[1] *
Correspondence
: adolfo.dq.ufmg@gmail.com

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Zika virus proteins at an atomic scale: how does structural biology help us to understand and develop vaccines and drugs against Zika virus infection?

Abstract