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Feature COGNITION STUDIO INC. STUDIO COGNITION CORONAVIRUS PIECE BY PIECE Biologists are working at breakneck speed to solve the structures of key SARS-CoV-2 proteins and use them against the virus. By Megan Scudellari ying in bed on the night of 10 January, West Lafayette, Indiana. “It’s what history has virus’s genome, seeking out the instructions scrolling through news on his smart- shown us.” for each of its estimated 25–29 proteins. With phone, Andrew Mesecar got an alert. In Lübeck, Germany, Rolf Hilgenfeld those instructions in hand, the scientists could He sat up. It was here. The complete stopped packing boxes for his retirement recreate the proteins in the lab, visualize them genome of a coronavirus causing a and started preparing buffers for crystal- and then, hopefully, identify drug compounds cluster of pneumonia-like cases in lography. In Minnesota, Fang Li stayed up all to block them or develop vaccines to incite the Wuhan, China, had just been posted night analysing the new genome and drafting immune system against them. online. a manuscript. In Shanghai, China, Haitao Yang “Here we go,” thought Mesecar. “I’d better LAround the world, similar notifications rallied a dozen graduate students to clear their get some sleep.” appeared on the devices of scientists who schedules. In Texas, Jason McLellan instructed first crossed swords with coronaviruses in laboratory members to start assembling gene 11 January: 41 confirmed cases of the 2003 outbreak of SARS (severe acute sequences from the viral genome. COVID-19 worldwide respiratory syndrome) and then again with Within 24 hours, a network of structural Mesecar woke at 6 a.m. the next day, turned on MERS (Middle East respiratory syndrome) biologists around the world had redirected the coffee pot and began blasting through the in 2012. Instantly, the researchers mobilized their labs towards a single goal — solving the new genome looking for recognizable protein against a new adversary. “We always knew that protein structures of a deadly, rapidly spread- sequences. It didn’t take long. He had spent this was going to come back,” says Mesecar, ing new contagion. To do so, they would need 17 years studying coronaviruses, and the new head of biochemistry at Purdue University in to sift through the 29,811 RNA bases in the virus’s genome looked very familiar. 252 | Nature | Vol 581 | 21 May 2020 ©2020 Spri nger Nature Li mited. All rights reserved. ©2020 Spri nger Nature Li mited. All rights reserved. “Holy shit,” he thought. “This is the same thing as SARS.” THE KEY CORONAVIRUS PROTEINS Right away, Mesecar contacted Karla Researchers are racing to visualize and understand the proteins used by SARS-CoV-2 to enter cells and replicate. That information could be crucial for making drugs and vaccines to stop the virus. Satchell, a microbiologist at Northwestern University in Chicago, Illinois. Satchell is The spike protein (closed) NATURE co-director of the Center for Structural Genomics of Infectious Diseases (CSGID), a consortium of eight institutions set up exactly for moments like this — to rapidly investigate Carbohydrates the structures of emerging infectious agents. cover the surface To solve the 3D structure of a protein at of the spike, disguising it from high resolution, scientists first design a gene S2 subunit the immune system. construct — a circle of DNA containing the , 281 (2020). GRAPHICS: NIK SPENCER/ , 281 (2020). S1 subunit 181 instructions for the protein, together with regulatory sequences to control where and how it is expressed. They then insert the ET AL. CELL construct into living cells, often the bacte- rium Escherichia coli, using the cells’ own The virus shell is covered in spikes Each spike carries The new virus binds each made of three identical three identical more strongly than machinery to churn out the desired protein. proteins. At the end of each spike binding domains, SARS does to cells, Next, they purify the protein so that they is a small binding region that locks all of which must even though the spike onto human cells. bind the host cell. shapes are similar. SOURCE: A. C. WALLS A. C. WALLS SOURCE: can visualize its structure using either of two methods. One is X-ray crystallography, which involves growing tiny crystals of pure the structures of two other coronavirus spikes Mpro in coronaviruses is made up of two protein and revealing their internal struc- — from HKU1, a cause of common colds1, and identical subunits and looks like a moth- ture by bombarding them with X-rays from from the MERS virus2. The work was done in eaten heart, with an active enzyme site on a high-energy electron beam. The other is collaboration with structural biologist Andrew each side of the structure. On 26 January, Rao cryo-electron microscopy (cryo-EM), a pro- Ward at the Scripps Research Institute in La and Yang submitted the Mpro structural data to cess of scanning flash-frozen proteins using Jolla, California, and virologist Barney Graham the Protein Data Bank (PDB), an open-access a high-powered electron microscope. at the US National Institute of Allergy and digital resource for 3D structures of biological Either process can take months, even years, Infectious Diseases’ Vaccine Research Center molecules. By 5 February, the data had been for an unfamiliar protein. Luckily, many of the in Bethesda, Maryland. So, the group knew how processed and the final structure was released new coronavirus proteins were familiar, with to tweak the spike protein’s genetic sequence online — not a moment too soon, says Yang. 70–80% sequence similarity to SARS-CoV, the so that it would stabilize in a pre-fusion shape The laboratory had already received an over- virus that caused the 2003 SARS outbreak. By — the form it adopts before it docks onto a host whelming 300 requests for the structure. 7:30 a.m., Mesecar and his team had begun cell. “Our ability to get this particular structure While working on Mpro, Rao contacted a designing gene constructs for the new viral was based upon all our prior knowledge from former co-worker, David Stuart, a structural proteins, and even predicted which of their working on HKU1 and MERS and SARS,” says biologist at the University of Oxford, UK, who existing coronavirus inhibitors might block McLellan. is life-sciences director at Diamond Light these proteins. While McLellan’s team waited for the Source, the United Kingdom’s synchrotron Satchell, who had been following early news construct to arrive, Graham called Moderna facility. The UK and Shanghai groups began reports about the virus, organized a virtual Therapeutics, a drug-discovery company in collaborating closely to share advice and meeting of consortium members to start Cambridge, Massachusetts, with which the avoid overlap, says Martin Walsh, deputy life- solving the virus’s proteins. “We’ve thrown Vaccine Research Center had been working sciences director at Diamond. “We keep each the weight of every investigator at every on a pandemic-preparedness project. On other up to date on things, and try to benefit site behind COVID,” says Satchell. Mesecar, 13 January — before any spike protein had from the different approaches they’re using a CSGID investigator, started with Mpro, the been made — Moderna began preparing its and we’re using.” virus’s main protease, an enzyme that cuts out manufacturing facilities to make a coronavirus Because the Shanghai team solved Mpro in proteins from a long strand that the virus pro- vaccine based on that protein. complex with an inhibitor, the Diamond team duces when it invades a cell, like a tailor cutting decided to focus on crystallizing the protein out pattern pieces. Without Mpro, there is no 26 January: 2,014 confirmed cases with no molecule attached, hoping to identify viral replication. Humans do not have a similar At ShanghaiTech University in China, Zihe Rao, active sites to which potential drug com- protease, so drugs targeting this protein are Haitao Yang and their colleagues worked day pounds might bind. Over two weeks, Walsh’s less likely to cause side effects. and night, sacrificing their week-long Chinese group ran 17,000 experiments to hit on the Lunar New Year holiday, to solve the Mpro struc- best recipe for precipitating the unbound 13 January: 42 confirmed cases ture and those of another trio of proteins that protein into a crystal. In McLellan’s molecular biosciences lab at the the coronavirus uses to replicate. University of Texas at Austin, graduate student Using X-ray data acquired at the Shanghai 1 February: 11,953 confirmed cases Daniel Wrapp spent the weekend designing Synchrotron Radiation Facility and the In Hilgenfeld’s lab at the University of Lübeck, a gene construct for another key protein — National Center for Protein Science Shanghai researcher Linlin Zhang had taken to phoning the outer, three-pronged spike that gives the — which both allocated special beam time the company making the Mpro gene construct coronavirus its crown-like appearance and for the project — the team solved the crystal daily until it finally arrived. Thanks to the lab’s name. Wrapp placed an order for the con- structure of Mpro bound to an inhibitor3. In experience crystallizing other coronavirus pro- structs with a commercial firm that Monday, 2003, it had taken them two months to solve teases, Zhang grew Mpro crystals in 10 days, and 13 January. the structure of the SARS-CoV main protease. on 1 February, she took the precious samples McLellan had been involved in determining This time, it took one week. to the BESSY II synchrotron in Berlin, which Nature | Vol 581 | 21 May 2020 | 253 ©2020 Spri nger Nature Li mited. All rights reserved.

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