Evolutionary potential of the SARS-CoV-2 receptor binding domain (RBD)

 

Jesse Bloom

Fred Hutch Cancer Research Center / UW Genome Sciences / HHMI

 

Slides at https://slides.com/jbloom/gs-retreat-2020​

 

@jbloom_lab

SARS-CoV-2 virions are decorated by spike proteins that mediate viral entry

A key portion of the spike is the receptor-binding domain (RBD)

The RBD binds ACE2 receptor on cells

Neutralizing antibodies often bind RBD & block interaction with ACE2

Yeast display to measure how mutations affect RBD folding and ACE2 binding

RBD

fluorescent ACE2

yeast

fluorescent tag on RBD

Library of yeast, each expressing different RBD mutant with identifying 16 nt barcode

Maps of how mutations affect RBD folding and ACE2 binding

We then mapped how mutations affect binding of anti-viral antibodies to RBD

core RBD

receptor-binding motif

ACE2-contact residue

Escape map from one antibody

(click here for interactive visualization)

core RBD

receptor-binding motif

ACE2-contact residue

Escape maps for three antibodies

Subtle differences between COV2-2165 & COV2-2832 (e.g., sites 486, 487) validate in neutralization assays (see here).

core RBD

receptor-binding motif

ACE2-contact residue

We can organize antibodies in space of escape mutations

Summary

  • We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity

Summary

  • We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity
  • These maps tell us how virus can escape from antibodies.

Summary

  • We can create phenotypic maps of how all mutations to SARS-CoV-2 RBD affect folding, function, and antigenicity
  • These maps tell us how virus can escape from antibodies.
  • The maps are useful for understanding how ongoing viral evolution affects therapeutic antibodies and immunity

Summary

Tyler Starr

Allie Greaney

Sarah Hilton

Bloom lab (Fred Hutch)

James Crowe

Seth Zost

Pavlo Gilchuk

Crowe lab (Vanderbilt)

Tyler Starr

Allie Greaney

Sarah Hilton

Bloom lab (Fred Hutch)

James Crowe

Seth Zost

Pavlo Gilchuk

Crowe lab (Vanderbilt)

Tyler Starr

Allie Greaney

Sarah Hilton

Bloom lab (Fred Hutch)

Bloom lab (Fred Hutch)

  • Kate Crawford
  • Adam Dingens
  • Andrea Loes
  • Rachel Eguia

 

Crowe lab (Vanderbilt)

  • Elad Binshtein

 

Whelan lab (Wash U)

  • Sean Whelan
  • Paul Rothlauf
  • Zhuoming Liu

 

King lab (Univ Wash)

  • Neil King
  • Dan Ellis

 

Veesler lab (Univ Wash)

  • David Veesler
  • Alexandra Walls

Interested in this work? Please see the following papers for more details:

gs-retreat-2020

By Jesse Bloom

gs-retreat-2020

The evolutionary potential of the SARS-CoV-2 receptor binding domain

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