Structural impact on SARS-CoV-2 spike protein by D614G substitution

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Science  30 Apr 2021:
Vol. 372, Issue 6541, pp. 525-530
DOI: 10.1126/science.abf2303

How an early variant got ahead

Throughout the COVID-19 pandemic, epidemiologists have monitored the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with particular focus on the spike protein. An early variant with an aspartic acid (D) to glycine (G) mutation at position 614, D614G, rapidly became dominant and is maintained in current variants of concern. Zhang et al. investigated the structural basis for the increased spread of this variant, which does so even though it binds less tightly to the host receptor (see the Perspective by Choe and Farzan). Structural and biochemical studies on a full-length G614 spike trimer showed that there are interactions not present in D614 that prevent premature loss of the S1 subunit that binds angiotensin-converting enzyme 2. This stabilization effectively increases the number of spikes that can facilitate infection.

Science, this issue p. 525; see also p. 466


Substitution for aspartic acid (D) by glycine (G) at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. Here, we report cryo–electron microscopy structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations that differ primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer—effectively increasing the number of functional spikes and enhancing infectivity—and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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