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Supergirl's new research on HIV
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HIV infection process and anti-HIV drugs
HIV genome is encoded by RNA, which is reverse-transcribed to DNA after entering a host cell. Then it is integrated into host's DNA, transcripted and translated to HIV proteins. HIV protease cleave them to produce mature infectious viruses, see Fig.1. The anti-HIV drugs have been developed to inhibit some enzymes essential for HIV replication, For example, HIV protease inhibitor are blocking the cleaving process so that it can only generate immature, non-infectious viral particles, see Fig.2. This leads to the successful development of HAART cocktail drug to combat HIV.
Fig.1 HIV infection process
Fig.2 How HIV inhibitor works
Xiaowei Zhuang's new research on HIV reverse transcriptase
The reverse transcriptase of human immunodeficiency virus (HIV) is never easy. it needs to discriminate a variety of nucleic-acid substrates such that active sites of the enzyme are correctly positioned to give the right DNA chain based on original RNA chain. How reverse transcriptase is doing not well-known. Zhuang Xiaowei's experiment shows how reverse transcriptase oriented itself with different nucleic-acid substrates. In article, it says "The enzyme adopted opposite binding orientations on duplexes containing DNA or RNA primers, directing its DNA synthesis or RNA hydrolysis activity, respectively. On duplexes containing the unique polypurine RNA primers for plus-strand DNA synthesis, the enzyme can rapidly switch between the two orientations. The switching kinetics were regulated by cognate nucleotides and non-nucleoside reverse transcriptase inhibitors, a major class of anti-HIV drugs. These results indicate that the activities of reverse transcriptase are determined by its binding orientation on substrates."[1]
Fig. 3 Zhuang's experiment set-up
Simply put, reverse transcriptase has two tasks:
1) Make DNA based on RNA, RNA here is the template
2) Make DNA from RNA fragments (PPT), RNA here is the raw material to make DNA
Question is: How reverse transcriptase behaves differently when the same RNA piece goes through it?
Answer By Zhuang: reverse transcriptase can change its shape in two situation, which is turned on or off by cognate nucleotides and non-nucleoside reverse transcriptase inhibitors.
Over-doze of these inhibitors will drive reverse transcriptase too crazy to make it right. So it is exactly how HIV drug is working. So Zhuang's work lead people to have a clear vision of working mechanism of the reverse transcriptase, and some new drugs which better target these sites can be developed. Supergirl did a super job again. :-)
Feynman's prediction comes true
Feynman once said that what Biology needs is to see better at the atomic Level:
" We have friends in other fields--in biology, for instance. We physicists often look at them and say, "You know the reason you fellows are making so little progress?" (Actually I don't know any field where they are making more rapid progress than they are in biology today.) "You should use more mathematics, like we do." They could answer us--but they're so polite, so I'll answer for them: "What you should do in order for us to make more rapid progress is to make the electron microscope 100 times better."
What Zhuang Xiaowei excels is exactly what Feynan predicted. If we want to understand the life, or the cell process, we just need to see what's going on for biological molecules at single molecular level.
Reference:
[1] Dynamic binding orientations direct activity of HIV reverse transcriptase, Nature 453, 184-189 (8 May 2008)
https://blog.sciencenet.cn/blog-3468-24595.html
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HIV genome is encoded by RNA, which is reverse-transcribed to DNA after entering a host cell. Then it is integrated into host's DNA, transcripted and translated to HIV proteins. HIV protease cleave them to produce mature infectious viruses, see Fig.1. The anti-HIV drugs have been developed to inhibit some enzymes essential for HIV replication, For example, HIV protease inhibitor are blocking the cleaving process so that it can only generate immature, non-infectious viral particles, see Fig.2. This leads to the successful development of HAART cocktail drug to combat HIV.
Fig.1 HIV infection process
Fig.2 How HIV inhibitor works
Xiaowei Zhuang's new research on HIV reverse transcriptase
The reverse transcriptase of human immunodeficiency virus (HIV) is never easy. it needs to discriminate a variety of nucleic-acid substrates such that active sites of the enzyme are correctly positioned to give the right DNA chain based on original RNA chain. How reverse transcriptase is doing not well-known. Zhuang Xiaowei's experiment shows how reverse transcriptase oriented itself with different nucleic-acid substrates. In article, it says "The enzyme adopted opposite binding orientations on duplexes containing DNA or RNA primers, directing its DNA synthesis or RNA hydrolysis activity, respectively. On duplexes containing the unique polypurine RNA primers for plus-strand DNA synthesis, the enzyme can rapidly switch between the two orientations. The switching kinetics were regulated by cognate nucleotides and non-nucleoside reverse transcriptase inhibitors, a major class of anti-HIV drugs. These results indicate that the activities of reverse transcriptase are determined by its binding orientation on substrates."[1]
Fig. 3 Zhuang's experiment set-up
Simply put, reverse transcriptase has two tasks:
1) Make DNA based on RNA, RNA here is the template
2) Make DNA from RNA fragments (PPT), RNA here is the raw material to make DNA
Question is: How reverse transcriptase behaves differently when the same RNA piece goes through it?
Answer By Zhuang: reverse transcriptase can change its shape in two situation, which is turned on or off by cognate nucleotides and non-nucleoside reverse transcriptase inhibitors.
Fig. 4 Two working modes of reverse transcriptase
Over-doze of these inhibitors will drive reverse transcriptase too crazy to make it right. So it is exactly how HIV drug is working. So Zhuang's work lead people to have a clear vision of working mechanism of the reverse transcriptase, and some new drugs which better target these sites can be developed. Supergirl did a super job again. :-)
Feynman's prediction comes true
Feynman once said that what Biology needs is to see better at the atomic Level:
" We have friends in other fields--in biology, for instance. We physicists often look at them and say, "You know the reason you fellows are making so little progress?" (Actually I don't know any field where they are making more rapid progress than they are in biology today.) "You should use more mathematics, like we do." They could answer us--but they're so polite, so I'll answer for them: "What you should do in order for us to make more rapid progress is to make the electron microscope 100 times better."
What Zhuang Xiaowei excels is exactly what Feynan predicted. If we want to understand the life, or the cell process, we just need to see what's going on for biological molecules at single molecular level.
Reference:
[1] Dynamic binding orientations direct activity of HIV reverse transcriptase, Nature 453, 184-189 (8 May 2008)
https://blog.sciencenet.cn/blog-3468-24595.html
上一篇：谈谈生物物理（4）--- 时间箭头与能量耗散
下一篇：Do what we can ...
