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Slack / Private Message Drop, p.327 [SLACK_000541] · slack_pm:msg:03443

Date: 2020-12-20 07:54
Type: chat message · slack
recipient: Kristian G. Andersen, Edward C. Holmes, Andrew Rambaut
speaker: Robert F. Garry
Topics: Furin cleavage site and molecular features

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Benton et al. is going to be the key to interpreting the NTD deletions and probably the other elephant mutations aswell. A pretty good interpretation of D614G therein. More importantly it clear that *both* NTD and the RBD need toundergo dramatic shifts that are driven by ACE2 binding to accommodate the S1/S2 and S2' cleavages and ultimately the large scale rearrangement of S2 into the 6 helix bundle. This doesn't rule out an NTD "receptor." Ineed to get to the office to look at the structures in Benton in a bit more detail to see what del69-70 etc do to theBenton structures, but it won't surprise me if they don't "destabilize" the trimer ala Doug.

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Statement	Grade	Attribution	Stance
More importantly it clear that both NTD and the RBD need toundergo dramatic shifts that are driven by ACE2 binding to accommodate the S1/S2 and S2' cleavages and ultimately the large scale rearrangement of S2 into the 6 helix bundle.	own voice, substantive	speaker_own	asserts

Statement

Grade

Attribution

Stance

More importantly it clear that *both* NTD and the RBD need toundergo dramatic shifts that are driven by ACE2 binding to accommodate the S1/S2 and S2' cleavages and ultimately the large scale rearrangement of S2 into the 6 helix bundle.

own voice, substantive

speaker_own

asserts

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2020-12-20 07:28 Robert F. Garry open

https://www.biorxiv.org/content/10.1101/2020.11.16.384743v1.full.pdf A couple of initial thoughts on the RBD changes. First, just to reiterate the dirty little "secret" of structural biologists - everything including cryoEM and X-raycrystallography are models - the resolutions are average and locally there is a lot of "fitting." That being said this figure from the Bullocks mink paper shows the residues in question E484 not to far from f486 obviously. Remarkable that N501 shows up in both the mink and the mouse. [shared file(s): image.png]
2020-12-20 07:28 Robert F. Garry open

https://www.nature.com/articles/s41586-020-2772-0
2020-12-20 07:54 Robert F. Garry

Benton et al. is going to be the key to interpreting the NTD deletions and probably the other elephant mutations aswell. A pretty good interpretation of D614G therein. More importantly it clear that *both* NTD and the RBD need toundergo dramatic shifts that are driven by ACE2 binding to accommodate the S1/S2 and S2' cleavages and ultimately the large scale rearrangement of S2 into the 6 helix bundle. This doesn't rule out an NTD "receptor." Ineed to get to the office to look at the structures in Benton in a bit more detail to see what del69-70 etc do to theBenton structures, but it won't surprise me if they don't "destabilize" the trimer ala Doug.
2020-12-20 07:59 Andrew Rambaut open

@Robert Garry I don't think 501Y turns up in mink.
2020-12-20 08:12 Robert F. Garry open

@Robert Garry It's N501T
2020-12-20 08:15 Robert F. Garry open

@Robert Garry Same residue changes to two diff amino acids when SC2 "adapts" to two diff animals.
2020-12-20 08:27 Robert F. Garry open

@Robert Garry In SC1 it's T501 fwiw.

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