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The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor. ### Competing Interest Statement P.C.S. is a co-founder and shareholder of Sherlock Biosciences, and a Board member and shareholder of Danaher Corporation. J.E.L. consulted for Sherlock Biosciences. C.A.K., K.E.P., and A.B. are employed by Regeneron Pharmaceuticals and own stock options in the company. C.A.K. is an officer at Regeneron. X.W., A.B., and N.D. are employees of Thermo Fisher Scientific.

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