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. 2022 Aug 24;609(7925):191–196. doi: 10.1038/s41586-022-05114-0

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© The Author(s) 2022, corrected publication 2023

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Extended Data Fig. 9 — In the RNA-bound (binary) complex, the central DNA binding channel is occluded by the REC2 and REC3 domains. Upon PAM recognition and initial 5-nt base pairing with the seed sequence of the guide RNA, the REC2 domain is displaced to form a binding cleft to accommodate the PAM-distal DNA duplex. Formation of 8-bp heteroduplex further displaces the REC3 domain and fully opens the central binding channel, while the PAM-distal duplex remains in the REC2/3 cavity. Extension of the R-loop to 10-bp heteroduplex places the guide-TS heteroduplex and the PAM-distal duplex into the central binding channel, accompanied by formation of electrostatic contacts between the REC2 and REC3 domains. Base pairing past the seed region results in undocking of the HNH domain from the RuvC and PI domain interface, and results in its repositioning towards target heteroduplex into the checkpoint state. R-loop formation past 17 base pairs induces REC2 domain displacement from the binding channel and rotation of the HNH domain active site towards the TS cleavage site, while simultaneously positioning the NTS in the RuvC domain active site.