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1、Viral Genome and Structures,Laboratory of Medical Molecular VirologyChang Liu,Viral Genome and StructuresLab,v.163/special/opencourse/virology.html,v.163/special/opencourse/virol,Breakthrough in 1950s,The viral nucleic acid genome carries the information needed to replicate, build, and spread virion
2、s in the world.One of the building blocks of Molecular BiologyT4, TMV,Breakthrough in 1950sThe vira,Hershey-Chose experimentwith phage T4,Fraenkel-Conrats work with TMV,Hershey-Chose experimentFraenk,Seven Genome Types,Either DNA or RNAStructurally diverse: linear, circular, segmented, gapped, singl
3、e-stranded (+) strand, single-stranded (-) strand, single stranded (ambisense), double-stranded, some have covalently attached proteins, some have cross-linked ends of double-stranded DNARNA World hypothesis,Seven Genome TypesEither DNA o,病毒的基因组与结构-医学资料,What information is encoded in a viral genome？
4、,Replication of viral genomeAssembly and packaging of the genomeRegulation and timing of the replication cycleModulation of host defensesSpread to other cells and hosts,What information is encoded in,Information Not contained in viral genomes,No genes encoding the complete protein synthesis machiner
5、yNo genes encoding protein involved in energy production or membrane biosynthesisNo classical centromeres or telomeres found in standard host chromosomes,Information Not contained in v,The Baltimore System,Viral genome must make mRNA that can be read by host ribosomes,The Baltimore SystemViral geno,
6、NOT all(+) RNA is mRNAEach way has unique polymerase, primer, template and termination requirementsEach virus family has its own characteristic genome strategy,NOT all(+) RNA is mRNA,Seven classes distinguished by genome replication strategies,ds DNA, ss DNA,Seven classes distinguished by,ds RNA, +s
7、s RNA, -ssRNA, Retro,ds RNA, +ss RNA, -ssRNA, Retro,dsDNA genomes,The problem of replicating the ends of linear DNA molecules through the use of RNA primers.,dsDNA genomesThe problem of re,Circular ds DNA genomes that are replicated in the nucleus,Circular ds DNA genomes that a,Linear ds DNA genomes
8、 that are replicated in the nucleus,Linear ds DNA genomes that are,病毒的基因组与结构-医学资料,Linear ds DNA genomes that are replicated in the nucleus,Linear ds DNA genomes that are,ds DNA genomes that are replicated in the cytoplasm,ds DNA genomes that are replic,ssDNA genomes,A basic problem with a ssDNA geno
9、me:RNA can only be made from a dsDNA template,ssDNA must be converted into dsDNA before mRNA is madeDNA synthesis must precede mRNA production,ssDNA genomesA basic problem w,Linear ss DNA genomes that are replicated in the nucleus,Linear ss DNA genomes that are,病毒的基因组与结构-医学资料,RNA genomes,Cells have
10、NO RNA-dependent RNA polymerases (RdRp) to replicate the genomes of RNA viruses, or to make mRNA from RNARNA virus genomes encode novel RdRpPolymerases produce both RNA genomes and mRNA from RNA templates+ssRNA, -ssRNA, dsRNA,RNA genomes Cells have NO RNA-,+ssRNA,Hepatitis A virus, foot and mouth di
11、sease virus, and rhinoviruses which cause the common cold. The coronaviruses which includes important veterinary viruses and the SARS virus. Hepatitis C virus. Yellow fever virus.,+ssRNAHepatitis A virus, foot,Positive-strand RNA viruses that make no subgenomic mRNAs,Positive-strand RNA viruses th,P
12、ositive-strand RNA viruses that make one or more subgenomic mRNAs,Positive-strand RNA viruses th,-ssRNA,RdRpReassortment: Influenza virus,-ssRNARdRp,Negative-strand RNA viruse,Negative-strand RNA viruse,Ambisense RNA viruse,Ambisense RNA viruse,Double-stranded RNA(dsRNA),Many dsRNA genomes are segme
13、nteddsRNA cannot be translated by ribosomes,Double-stranded RNA(dsRNA)Many,ds RNA viruses,ds RNA viruses,Retrovirus,HIVHTLVIntegrate into the host DNAHBV,RetrovirusHIV,Retroviruses,Retroviruses,Hepadnaviruses,Hepadnaviruses,Structure,Nanometer: 10-9 metersAtom: 0.2-0.3 nm diameterAlpha helix in prot
14、ein: 1 nm diameterDNA: 2 nm diameterRibosome: 20 nm diameterPoliovirus: 30 nmMimivirus: 750 nm,StructureNanometer: 10-9 mete,病毒的基因组与结构-医学资料,病毒的基因组与结构-医学资料,病毒的基因组与结构-医学资料,Functions of virion proteins,Protection of the genomeAssembly of a stable, protective protein shellSpecific recognition and packag
15、ing of the nucleic acid genomeInteraction with host cell membranes to form the envelope,Functions of virion proteinsPr,Delivery of the genomeBinding to host cell receptorsTransmission of signals that induce uncoating of the genomeInduction of fusion with host cell membranesInteraction with cell comp
16、onents to direct transport of genome to the appropriate sit,Delivery of the genome,Other interactions with hostWith cell components to ensure efficient infectious cycleWith cell components for transport to sites of assemblyWith the host immune system,Other interactions with host,Virus particles are
17、not inert structures,Virions are metastable structures: have not attainted minimum free energy conformationGained only when an unfavorable energy barrier is surmounted, following irreversible conformational changes during attachment and entryViruses are molecular machines that play active role in de
18、livery of genome,Virus particles are not inert,To be infectious, the particles must be metastableMust protect the genome (stable)Must come apart quickly on infection (unstable)An infectious virion is a molecular machineHas moving parts and does work,To be infectious, the particle,Virion structure an
19、d function,Structure (the particles; the virion)Created by symmetrical arrangement of many identical proteins to provide maximal contact and non-covalent bondingFunction (genome delivery)Made possible because the structure is Not permanently bonded togetherCan be taken apart or loosened on infection
20、 to release,Virion structure and functionS,The tools of viral structural biology,Electron microscopyX-ray crystallographyCryo-electron microscopyNuclear magnetic resonance spectroscopy (NMR),The tools of viral structural,TITLE: Artificial Nano “T4 Bacteriophage”Description: “T4 Bacteriophage” is a v
21、irus like the robot in the living body.Artificial nano “T4 Bacteriophage” was fabricated by FIB-CVD on Si surface.Size of the artificial nano “T4 Bacteriophage” is about ten times as large as the real virus.It is made of Diamond-like Carbon. It is likely to begin to walk in the nano space! Magnifica
22、tion: 25,000XInstrument: SII NanoTechnology Inc. / SMI2050MS2Submitted by: Reo Kometani & Shinji Matsui (University of Hyogo),TITLE: Artificial Nano “T4 Bac,Structure of Reovirus Core Determined Via X-ray Crystallography,Structure of Reovirus Core Det,Enveloped viruses and coated vesicles cryo-elect
23、ron microscopy and tomography,Enveloped viruses and coated v,Herpes virus protein (red) docks with human cellular protein (white),UK scientists have used solution-state NMR spectroscopy for the first time to develop a 3D picture of a herpes virus protein interacting with a key part of the human cell
24、ular machinery. The study improves our understanding of how the virus hijacks human cells and could eventually lead to new targets for drug therapy.,Herpes virus protein (red) doc,Principles of building virions: Symmetry is key,Watson and Crick did more than discover DNA structure1956: pointed out t
25、hat most virus particles were spherical or rod-shaped in the EMKnew particles were made with many copies of few proteins (genetic economy)Viral proteins have structural properties that permit regular and repetitive interactions among them,Principles of building virions,They provide rules for “self-a
26、ssembly”,Rule 1: Each subunit has “identical” bonding contacts with its neighborsRule 2: These bonding contacts are usually non-covalent,They provide rules for “self-a,Many capsid proteins can self assemble into “virus-like particles” (VLPs)The HBV and HPV vaccines are VLPs made in yeast,Many capsid
27、 proteins can self,Helical symmetry,Helical symmetry,病毒的基因组与结构-医学资料,Enveloped virions of RNA viruses with ssRNA genomes with helical capsids,Paramyxoviridae (measles virus)Rhabdoviridae (rabies virus）Orthomyxoviridae (influenza virus)Filoviridae (Ebola virus),Enveloped virions of RNA virus,How can y
28、ou make a round capsid from proteins with irregular shapes?,Clue1: All round capsids have precise numbers of proteins; multiples of 60 are common (60, 180, 240, 960) (T number)Clue 2: Spherical viruses come in many size, but capsid proteins are 20-60 kDa average,How can you make a round capsi,病毒的基因组
29、与结构-医学资料,病毒的基因组与结构-医学资料,病毒的基因组与结构-医学资料,病毒的基因组与结构-医学资料,病毒的基因组与结构-医学资料,Triangulation number, T,Triangulation number, T,Quasiequivalence,Quasiequivalence,Structurally complex capsids,Structurally complex capsids,病毒的基因组与结构-医学资料,Capsid can be covered by host membranes: enveloped virions,Enveloped virions
30、 are common, particularly those that infect animalsEnvelope is lipid bilayer derived from host cell Envelope acquired by budding of nucleocapsid through a cellular membrane,Capsid can be covered by host,Assembly of helical nucleocapsidsAssembly of isometric nucleocapsidsAcquisition of the lipid enve
31、lope,Assembly of helical nucleocaps,Other virion components,EnzymesPolymerases, integrases, proteases Activators, mRNA degradation, required for efficient infection, mRNACellular components:Histones, tRNAs, myristate, lipid,Other virion componentsEnzymes,VIPERdbViperdb.scripps.edu,VIPERdb,69,谢谢！,69谢谢！,
