3D Atomic Structures of a key complex in paramyxoviruses Mapped
For the first time, the 3-D atomic structure of a key complex in paramyxoviruses (a family of viruses that includes measles, mumps, respiratory syncytial virus (RSV) and human parainfluenza) has been determined by researchers at the Northwestern University.
Scientists can use this information which would aid in designing and developing antiviral drugs for these viruses and also for viruses that function similarly to paramyxoviruses like coronavirus.
Northwestern’s Robert Lamb, who co-led the study said, “This eliminates some of the guesswork out of designing drugs because traditionally, drugs are to be developed randomly and hope you hit a target, but it happens very rarely.”
The scientists made use of cryogenic electron microscopy (cryo-EM) to find the unique structure. Determining the 3-D shape of proteins is enabled by this relatively new technique. Researchers majorly used X-ray crystallography before cryo-EM. Capturing high-resolution images of this enzyme was not possible using X-ray crystallography.
Northwestern’s Yuan He, who co-led the study said, “Only for very orderly and organized proteins, crystallography works. Virus polymerase complexes don’t have uniformity and are too big to be crystallized.”
Researchers did not have the equipment to characterize the atomic structure of mumps and measles until relatively recently even though the first documented case of mumps occurred in the 5th century and measles in the 9th century. A Nobel Prize in Chemistry for developing cryo-EM was bagged by a trio of biophysicists in 2017, which helped Lamb and He in this study.
The working of Cryo-EM involves taking many 2-D images by blasting a stream of electrons at a flash-frozen sample. Several images of human parainfluenza virus 5 polymerases’ sample, were captured by He and his team. To reconstruct the image, computational algorithms were used.
A round-shaped globule, that was irregular and had a long tail made of four proteins containing phosphorous or phosphoproteins, was the resulting image. There were more than 2,000 amino acids and five proteins in the structure.
The atomic structure of a polymerase in human parainfluenza virus 5. Credit: Northwestern University
Lamb said that they had expected one part of the image but another part of it was a surprise as they observed two completely new proteins that they have never seen before.
There was also another surprise, the team identified that the same protein to switch between genome replication and transcription was used by this virus.
For illnesses such as mumps and measles, Lamb and He hope this work can aid others in designing and developing new drugs.
Lamb said, “A lot of people are getting the disease as they do not want to get vaccinated. However, it still takes 3-4 weeks for that vaccine to start acting in the people who are vaccinated. For treated the infected people immediately, we need more antiviral drugs.”
The Proceedings of the National Academy of Sciences published this study.
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