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Frontiers in infectious diseases > 4. Virus Structure > Flashcards

4. Virus Structure Flashcards

1
Q

What is the virus structure important for?

A

How the virus enters cells

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2
Q

What are viruses?

A

Simple packets of genetic information

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3
Q

What are the most simple viruses?

A
  1. They contain nucleic acid.
  2. They are surrounded by repeats of the same coat protein.
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4
Q

What are non-enveloped viruses?

A
  1. Viruses made only of the nucleocapsid.
  2. They can contain many different genome segments.
  3. They contain more proteins than the simplest viruses but still quite simple.
  4. Repeated units of the protein give it symmetry.
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5
Q

What are enveloped viruses?

A
  1. There are more complex viruses.
  2. They obtain a lipid bilayer from the host cell.
  3. This surrounds the capsid.
  4. Viral spike proteins can be embedded into it. These proteins are important for viral entry.
  5. The envelopes are very fluid structures so can look different.
  6. The symmetry of the virus is in the nucleocapsid not in the membrane.
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6
Q

What is the nucleocapsid?

A

The genetic information and the coat protein

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7
Q

What creates the symmetry in the virus particle?

A

The repeated protein units.

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8
Q

What are the 2 types of symmetry in viral particles?

A
  1. Icosahedral
  2. Helical
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9
Q

What is icosahedral symmetry?

A
  1. It is a way to create a maximum volume with the smallest surface area.
  2. It is an efficient way to make that particle with the fewest proteins.
  3. The simplest icosahedrons have 20 triangular faces related with 2, 3 and 5 fold symmetry.
  4. The faces can be made up of several different proteins.
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10
Q

What is helical symmetry?

A
  1. The simplest shape and symmetry a virus can have.
  2. They form with RNA genomes and 1 protein surrounding it.
  3. This forms the symmetrical structure.
  4. Often animal RNA viruses have a nucleocapsid surrounded by a fluid membrane which takes on helical symmetry.
  5. The symmetry often comes from the nucleocapsid.
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11
Q

What are the main methods of studying virus structure?

A
  1. Electron microscopy
  2. Cryo-electron microscopy
  3. X-ray crystallography
  4. Cryo-electron tomography
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12
Q

What is electron microscopy?

A
  1. A high resolution microscope used to take pictures of biological structures.
  2. Required negative staining for virus particles for see them.
  3. Resolution of around 50-70Å
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13
Q

How is electron microscopy used to study virus structure?

A
  1. It is used to look for symmetry in viral particles and see projections from the viral surface.
  2. You can define some surface structure or some morphological units.
  3. Can be used to diagnose viral infection in combination with symptoms.
  4. Used to see the size of the virus
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14
Q

What is the disadvantage of electron microscopy in studying virus structure?

A

Negative staining can distort the virus structure.

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15
Q

How does Cryo-EM work?

A
  1. Take a preparation of virus particles and rapidly freeze them.
  2. This freezing happens too quickly for ice crystals to form, so you can get a glass-like layer.
  3. The particles in this layer can be imaged with EM.
  4. A complex maths model collects the symmetry of the molecules to build a 3D computational model of the virus structure.
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16
Q

What is required for Cryo-EM to work?

A
  1. Symmetry in the virus.
  2. A good concentration of virus particles.
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17
Q

How is Cryo-EM used to study the virus structure?

A
  1. The rapid freezing preserves the native structure of the virus.
  2. Due to the higher resolution you can see some contrast in the morphological units of the proteins. You can count them and see if they are made up of smaller repeated units.
  3. make 3D reconstruction of the virus.
  4. Advancements in technology means it can see viruses at atomic resolution.
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18
Q

What does seeing a virus at an atomic level resolution allow us to do?

A

It allows mapping the interactions between different amino acid side chains or with drugs.

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19
Q

How is X-ray crystallography used to study the structure of large viruses?

A
  1. It can’t be used to study whole large viruses.
  2. But it can be used to study components of the virus like an adenovirus hexon.
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20
Q

How is X-ray crystallography used to study the structure of small viruses?

A
  1. It can be used to study small viruses.
  2. The virus needs to be able to form crystals
  3. The first high resolution structure was determined in 1978.
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21
Q

How has cryo-EM technology advanced?

A
  1. This technology has advanced massively.
  2. Now has a really good resolution of up to 1.6Å.
  3. These microscopes cost millions.
  4. The different imaging systems and general technological advances have allowed the resolution to improve.
  5. You don’t need to crystallise the proteins and it can be applied to the whole virus.
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22
Q

How was cryo-EM used to study Zika virus?

A
  1. in 2016 the most advanced (for the time) cryo-EM of Zika was taken at 3.8Å
  2. Zika is a Flavivirus
  3. This is not quite atomic level so it was combined with X-ray crystallography.
  4. It was so advanced that it could be used to look at side chains and amino acids.
  5. It can be complimented with AI.
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23
Q

What is cryo-electron tomography and how is it used to study viruses?

A
  1. It combines cryo-preservation with electron tomography.
  2. Can be used to study larger viruses and non-symmetrical viruses like vaccinia virus.
  3. It is time-consuming to take the images and reconstruct the structure, so it is used less often.
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24
Q

How does cryo-electron tomography work?

A
  1. Take a cryo-EM and tilt it to take cross sections.
  2. Reconstruct these into a virus structure.
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25
Q

What is cryo-focused iron bead milling?

A
  1. It is a new way to look at viruses within cells.
  2. You can take a cell and reconstruct the virus within them.
  3. Visualisation in living cells
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26
Q

What is alpha fold?

A
  1. An AI program that can predict the structure of a protein from the nucleotide sequence.
  2. This uses experimentally determined protein structures to predict the structure of unknown proteins.
  3. This means we can predict unknown viral protein structures from the nucleotide sequence. eg for a novel pathogen.
  4. It now contains structural predictions for >200 million proteins.
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27
Q

How can AI be used to advance our knowledge of virus structure?

A
  1. Refining cryo-EM structures and combining particle and protein structure to fit the predicted structure.
  2. Predicting viral protein structure based on the nucleotide sequence
  3. Determining evolutionary relationships between viruses based on viral structural protein structures.
  4. Predicting the effect of amino acid changes in virus structural proteins on receptor and antibody binding.
  5. In silico drug screening.
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28
Q

What are AI structures of proteins based on?

A

Many years of experimentally determined structures.

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29
Q

What was the 1st viral structure to be determined?

A

Poliovirus

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30
Q

What is poliovirus?

A

A non-enveloped picornavirus

31
Q

How was the structure of poliovirus determined?

A
  1. It has no envelope and is very symmetrical so it can be crystallised.
  2. X-ray crystallography determined there are 4 proteins in the virus capsid with 3 on the surface.
  3. The faces of the icosahedron are made up of different proteins.
32
Q

What structures were determined in poliovirus?

A
  1. Icosahedral shape
  2. The X-ray determined a ß-jelly role structure.
33
Q

What is the ß-jelly role structure?

A
  1. 8 ß-sheets that roll up into a jelly roll.
  2. These role up into a block like structure.
  3. The central cores are similar between the proteins.
  4. The loops vary for the different structural proteins in poliovirus.
  5. The ß core is important for building the virus structure.
34
Q

What are the similarities between poliovirus and adenovirus?

A
  1. They have similar core protein subunits.
35
Q

What are the differences between poliovirus and adenovirus?

A
  1. Polio is RNA and adenovirus is DNA
  2. Polio is small and adenovirus is very big
36
Q

What can we tell about viruses based on their structure?

A
  1. The evolutionary relationship between different viruses.
  2. Evolving similar proteins makes sense as there is an optimal way to do things.
  3. Viruses can pick up other proteins that can give them new structures.
37
Q

What is the influenza virus H protein?

A

Haemagglutinin

38
Q

What is the influenza virus N protein?

A

Neuraminidase

39
Q

What is the structure of influenza virus?

A
  1. Looks spherical due to the fluid membrane structure.
  2. Has an icosahedral inner structure.
  3. Cannot crystallise due to the fluidity and lack of symmetry.
40
Q

What is the structure of haemagglutinin?

A
  1. contains ß-sheets and helices
  2. Contains a receptor binding domain and stalk domain.
  3. Starts as a large protein and then cleaved to actvate.
41
Q

What is the receptor binding domain of haemagglutinin?

A
  1. A globular structure
  2. Binds to sialic acid
  3. There are different HA1 structures for binding to different sialic acids.
  4. This structure determines the likelihood of the flu to spread through different animals
  5. This is also where antibodies can bind
42
Q

What is the Stalk domain of haemagglutinin?

A
  1. Contains a fusion peptide that is important for cell entry.
  2. has a transmembrane domain to bind the head to the surface of the virion.
  3. Also where antibodies can bind
43
Q

Do viral proteins change as conditions change?

A

yes

44
Q

Does haemagglutinin change as the surrounding conditions change?

A
  1. It is a very dynamic protein
  2. Different conditions change the conformation
  3. These conditions can be pH or if the virus is pre or post fusion
  4. The conformation change based on conditions can trigger rearrangements needed for virus entry.
45
Q

Can viral conformation changes be mapped?

A
  1. Yes
  2. You can make molecular dynamic simulations
  3. This is mostly driven by AI
  4. They show the movement and binding of receptors.
46
Q

What is the Flavivirus lifecycle?

A
  1. The virus enters the cell.
  2. The RNA genome is translated into a polyprotein that is cleaved to make mature proteins.
  3. The virus is assembled in the ER.
  4. When the virus is assembled, it goes through the secretory pathway and is released.
  5. The immature virion has a spikey protein on the outside.
  6. The mature virion forms once it is released from the cell and has a smooth outside.
47
Q

How do Flaviviruses enter the host cell and why does this require the virus to have an immature form?

A
  1. Entry is important and flaviviruses do this by receptor mediated endocytosis.
  2. When the virus enters the cell there is a pH change which causes structural rearrangement.
  3. You don’t want this rearrangement to happen as the virus is leaving the cell so it the spiky outer structure.
  4. The spiky layer is protective and prevents fusion to the host cell membrane when it is released, so the virus can resist the pH change.
48
Q

How is the Flavivirus envelope formed?

A
  1. When the virus is translated, it produces a capsid protein, envelope proteins, pre-membrane proteins (prM) and other non-structure proteins.
  2. The capsid protein binds the RNA genome.
  3. prM and the envelope protein are on the outside of the virus structure.
  4. These proteins are threaded through proteins in the ER membrane so the virus is replicated on the ER membrane.
  5. The proteins are then cleaved by viral or host proteins.
49
Q

How do Flavivirus change from immature virion to mature virion?

A
  1. The prM makes the immature spike structures by pushing out the envelope proteins.
  2. The prM is cleaved to form the mature virion with a flat surface.
  3. This occurs just before the virus leaves the host cell.
  4. This is mostly done by the host enzymes, furin.
50
Q

How was the Flavivirus envelope protein structure discovered?

A
  1. from the X-ray crystal structure from the Tick-borne encephalitis virus.
  2. This was being isolate to make vaccines.
  3. The E protein was cleaved from it surface to determine the structure.
51
Q

What is the structure of the Flavivirus envelope protein?

A
  1. It is made up of 3 domains.
  2. Domain 1 is the central domain.
  3. Domain 2 is the fusion domain that contains a fusion loop.
  4. Domain 3 is the receptor binding domain.
52
Q

How does the Flavivirus envelope protein form the envelope surface?

A
  1. It forms a head to tail dimer which is 2 E proteins in opposite directions.
  2. They lie parallel to the virion membrane creating a flat structure which is important for virus entry.
53
Q

When was the Flavivirus E protein structure determined?

A

In 1995 at atomic level resolution

54
Q

What did the initial cryo-EM structure of the mature Dengue virus particle show?

A
  1. Determined in 2002 at 20Å resolution.
  2. the surface of the virus looked smooth.
  3. There were different layers arranged in a very tight protein structure.
  4. It was predicted to be arranged in an icosahedral structure although it didn’t really look that way.
55
Q

How was the icosahedral structure of Dengue confirmed?

A
  1. They took X-ray crystallography structure and fitted it into the Cryo-EM structure.
  2. Showed the icosahedral shape, symmetry and the E head to tail dimer that forms that surface.
  3. Now we could add alpha fold use to refine the structures.
56
Q

How do conditions in the cell influence the Flavivirus immature particle?

A
  1. Conditions in the cell include low pH.
  2. The particle is loosely packed.
  3. The particle is spikey due to the prM protein capping the envelope protein as it leaves the cell.
57
Q

How do the conditions influence the Flavivirus mature particle?

A
  1. As the virus is released from the cell the pH becomes more neutral. This makes the virus structure more compact.
  2. The pH drops again as the virus fuses with the cell.
  3. The opens up the virus structure which exposes lipids in the virus so it can interact with the host cell lipids.
  4. This helps the virus fuse with the host cell.
58
Q

How can we experimentally see how viruses change in different conditions?

A
  1. Viruses are dynamic structures.
  2. We can use various methods to take snapshots of viruses in different conditions.
  3. We can pull all this information together to see how viruses interact with the host.
59
Q

What is rational drug design?

A

The development of medications based on the study of the structures and functions of target molecules

60
Q

What is the influenza virus Neuraminidase protein?

A
  1. The N protein is a tetramer that can also bind and cleave sialic acid.
  2. It has an enzyme active site that is identical in all strains of influenza A and B.
  3. This makes it a good drug target.
61
Q

How were flu treatment developed using rational drug design?

A
  1. In silico screening against N protein with molecules that mimic sialic acid.
  2. These were turned into inhibitors that block viral entry to the cell. This is a key step in viral replication.
  3. These were further developed into Zanamivir (Tamiflu) and oseltamivir.
62
Q

How was rational drug design applied to SARS-CoV-2?

A
  1. The spike protein of SARS-CoV-2 was determined quickly.
  2. It was found that linoleic acid bound to the spike protein.
  3. It needs to be determined what the consequences or binding are and if it is important for viral entry.
  4. Also determine if it doesn’t bind.
  5. Could linoleic acid be used as a treatment?
63
Q

What is structure-based vaccine design?

A
  1. The binding of neutralising antibodies to the viral surface can be mapped.
  2. This is useful but can only be applied to 1 E protein at a time and is not very high resolution.
  3. It can show how antibodies bind to different viral antigens and how changes in these antigens effect this.
  4. It can determine which antibodies provide the best protective immune response.
64
Q

How can Cryo-EM be use together with antibody mapping?

A
  1. Take a Cryo-EM of the virus with antibodies bound to it.
  2. You can see specifically where the antibodies bind to the surface.
  3. They bind particular points and you can start to define the molecular contact.
  4. It can show if single mutations can alter antibody binding.
  5. Can be used to define antibody epitopes
65
Q

How was structural based vaccine design used to develop a vaccine for RSV?

A
  1. B cell clones were used to determine which antibodies are the best at neutralising the virus. this was the F glycoprotein.
  2. The antibody epitope site and structure was determined.
  3. The structure of the antibody epitope protein is stabilised to it can make a potential immune response when in a vaccine.
  4. The stabilised protein is made into the RSV vaccine.
  5. This same process was used to make the Covid mRNA vaccines.
66
Q

Are all antibodies produced by the body helpful?

A
  1. Neutralising antibodies are helpful
  2. Other antibodies are less helpful
  3. You want the antibodies that direct the immune response to the virus.
  4. These are potent neutralising antibodies
67
Q

How can the virus structure be used to map virulence determinants?

A
  1. Look for virus structure and mutations and properties in it.
  2. Mapping sequence changes on the structure shows what structures are important for determining different properties.
  3. Not all strains have the same properties.
68
Q

How is rational attenuation and mapping of virulence determinant used to vaccine design?

A
  1. This is used to develop live attenuated vaccines.
  2. If you know which residue determines the virulence of a strain you can direct mutations to attenuate the strains.
  3. Sometimes one amino acid change can make a virus much less virulent.
69
Q

What is the Flaviviridae virus family?

A
  1. A large family of viruses.
  2. It contains lots of variation with it.
  3. Includes Dengue, yellow fever virus, tick borne encephalitis virus and hepatitis C virus.
70
Q

How is Flavivirus classification determined?

A
  1. It is based only on conserved parts of the genome.
  2. There is not much information on the virus structure and how they are related.
  3. Most structures are not well conserved.
71
Q

What are large Flavi viruses?

A
  1. These have significantly larger genomes.
  2. They infect flies.
  3. We know nothing about the genome or structure
72
Q

How do Flaviviruses encode their proteins?

A

As 1 large polyprotein that gets cleaved to make separate proteins.

73
Q

How was AI used to look at Flavivirus structures and evolutionary relationships?

A
  1. They chopped the polyprotein into 300 amino acid chunks and used AI to predict the different structures.
  2. They did this for over 400 different flaviviruses.
  3. Certain structures were similar across Flaviviruses.
  4. The structures were compare in lots of in silico assays.
  5. Found similar structures in some viruses and distinct characteristics in others.
  6. This showed new ways flaviviruses are related in terms of structure.

Frontiers in infectious diseases (4 decks)

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