Molecule, Protein Shapes of proteins in living things: Molecules of COVID-19 生命を支えるタンパク質の形 －新型コロナウィルスのタンパク質 (14 min）
. We are developing. A database of protein 3D shapes Protein Data Bank. Each protein has its own 3D shape.. A protein 3D shapes tells us its biological function and gives us a key to develop drugs and vaccines.. We have created a special WEB page of the shapes of the corona viruses proteins.. We will briefly explain these proteins in the WEB page.. This is the 3D map of the corona virus, particle determined by electron microscopy. Clicking one of these buttons. You can turn on and off the parts of the particle.. This particle is made up of three parts. 1 spike proteins for protruding parts, 2, lipid membrane and 3. Rnp RNA and N proteins. Among the three the spike protein plays a very important role in infection. RNP stores, the genetic information as a single stranded RNA.. This page explains about basics, about 20 amino acids for proteins. A protein is a long chain of many amino acids.. There are 20 amino acids in nature., They have different sizes and shapes.. Some amino acids are soluble in waters. Some are not.. Each amino acids has a unique one letter alphabet., For example, isoleucine is I and valine is V.. If we use one letter, alphabet notation a following protein with eight amino acids can be represented by eight alphabets. SAVLQSGF.. This string is called amino acid sequence.. The spike protein of the corona virus is very long.. It has 1273 amino acids. By one letter notation. This is represented by 1273 characters like this.
Next lets. Think about the mutation called N501Y.. N501Y means that asparagine N in the 501 st site, changes into tyrosine Y. The asparagine N in the 501 st site is shown in blue. N501Y is changing this blue N to the tyrosine Y. This is the amino acid sequence of the original spike protein. This is the sequence of the mutated spike protein by N501Y.. Their difference is only one letter.. This is a slight difference, but asparagine N and tyrosine Y are quite different in shape. Also, as will be explained later, the 501st N is located on the top of the spike it can bind directly to human receptors.. This site is important for infection.. That is why this mutant N501Y greatly changes the infectivity.. This is the spike that corresponds to the protrusion part on the virus. Particle surface., The brown disk below is the virus lipid membrane.. The spike is made up of the same three protein chains.. We call them chain A chain B and chain C. When the virus starts to the infection. The receptor binding domain RBD play an important role. After binding to the receptors. The head S1 region is cut off and separated. Spike proteins are actually very soft and flexible molecules., Especially the three receptor binding domains. Rbds on the top can have both closed and open conformations.. In this all close structure, all the three RBDs has closed forms., Whereas this One open structure, one of the RBDs, has an open form.
, And this Two open structure, two of the RBDs, have open form.. Thus, a spike protein can has various conformations, such as all close One open Two open.. This conformational change is important for binding to human receptors and antibodies.. There are two spikes on the virus surface. On the top of them. A human cell approaches a human receptor. Protein called ACE2 binds to the spikes.. This is the first step of the infection.. This blue disk on the top is a human cellular membrane.. The brown disk at the bottom is a virus membrane envelope. After binding of the spike and the receptor, the human membrane and the virus membrane get closer and fused., And the virus enters into the human cell. When a virus enters into a human body. The human immune system produces a special attacking protein antibody.. They are antibodies.. This antibody protein binds to the spike protein and prevents the spike from binding to the human receptor protein.. You can see here. Three antibodies are bound on the spike.. There are a huge amount of variants of antibodies.. Each antibody has its own binding molecules and binding sites., For example, this another antibody, 1 87 binds to different region of the spike NTD domain.. The binding sites of the first antibody C002 and those of the second antibody 1 87 are completely different. In nature. Antibodies are produced after infection to human body.. A vaccination leads to the same effect.. The standard mRNA vaccine has a RNA molecule encoding the full length spike protein.
After injection of an RNA vaccine. A human cell translates many spike proteins from the RNA molecule in the vaccine.. Then the human immune system starts to produce antibodies which bind to the spike proteins. Most of the antibodies inhibit the spike to bind to human receptors and can protect us against disease. Antibody cocktail therapy is injection of multiple artificially extracted antibodies into the body to protect us From disease., This is a structure of spike with two antibodies cashiribimab and imdebimab.. The green molecule is Kasilibimab and the red molecule is Imdebimab.. The binding of the antibodies inhibits the spike to bind to human receptors and prevent us from disease.. You can see that two antibodies bind to different separated parts of the spikes.. It means that the two antibodies can be bound to one spike protein at the same time.. The combination of these two antibodies means the more amino acids of the spikes are recognized by the antibodies aims to decrease the chance of the virus escape mutants.. Many variants are reported for the corona virus, for example alpha variant and delta variant.. These variants are mainly characterized by a change in the amino acid mutation in the spike protein., For example, lets focus on the N501Y mutation in the alpha variant.. If you click the button N501Y, the site N501 is represented as red balls.. The site N501 is located in the binding site of the human receptor ACE2.. This mutation may enhance binding to the receptor.
. The site N501 is also close to the binding site of the antibody. This mutation may affect the binding to the antibody.. Similarly, the site T478 found in the mutations of the delta variant is close to the binding site of ACE2.. On the other hand, the mutation at the site P681 is found in the delta variant.. The site P681 is far from the binding sites of receptors and antibodies.. This mutation cannot directly affect the binding., But, as we mentioned previously for the entry of virus to human cell, the head region S1 has to be cut off.. The cleavage site S1S2 is now shown in green balls.. The site P681 is very close to the cleavage site.. The cleavage of S1S2 may be more likely to occur due to this mutation.. This is a RNA dependent RNA polymerase, an enzyme of corona virus.. This protein is made up of a large catalytic subunit and and two small accessary factors. In the center of the protein. A double stranded RNA is bound.. Many living organisms store their genetic information in double stranded, DNA.. In contrast, the corona virus stored its genetic information in single stranded RNA.. This green template RNA contains a part of the viral genetic information.. The polymerase helps to synthesize a blue, complementary primer RNA using the template RNA. At the head of the primer RNA remdesivir binds to prevent further elongation of the primer RNA.. The remdecivir forms a base pair with uracil 10U in the template.
Rna mimicking adenosine base.. Thus, the remdesivir interferes with the synthesis of the corona virus RNA and prevents disease.. Similarly, the molecule Avigan favipiravir also can bind to the primer RNA.. This molecule is Avigan. In this structure. Avigan forms a base pair with cytosine 10C in template, RNA mimicking guanosine base. Avigan. Can also interfere with the synthesis of RNA.. This is 3C, like protease the enzyme protein of the corona virus.. This protein is made up of two identical protein chains. After the entry into human cell, the corona virus. Let the human cell to synthesize a very long protein called polyprotein 1ab with 7096 amino acids., then cleaves the long protein into 15 proteins., One of the enzymes that cleaves the long protein is 3C like protease.. The yellow string, like molecule bound here, is the substrate protein to be cleaved. This is a part of the polyprotein 1ab. Only 8 amino acids were extracted from the 7096 amino acids.. The site between the 5th and 6th amino acids is the cleavage site by the 3C. Like protease. 3C, like protease, is a potential drug target for covid 19., For example. This molecular inhibitor N3 bind to the binding site of the substrate protein.. Then the protease cannot cut off other proteins. The virus cannot make a copy of itself.. Similarly, the inhibitor boceprevir binds to the binding site of the substrate protein.. Many pharmaceutical companies are now developing inhibitor chemical compounds.. Did you enjoy the 3D shape of proteins? The protein 3D shapes shown in this video can be seen in the WEB page by your computer or tablet.
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