Kunach P, Vaquer-Alicea J, Smith MS, Hopewell R, Monistrol J, Moquin L, Therriault J, Tissot C, Rahmouni N, Massarweh G, Soucy J-P, Guiot M-C, Shoichet BK, Rosa-Neto PK, Diamond MI, Shahmoradian SH. Cryo-EM structure of Alzheimer disease tau filaments with PET ligand MK-6240. 2023 Sep 22 10.1101/2023.09.22.558671 (version 1) bioRxiv.

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  1. This preprint by Kunach et al. describes a beautiful 2.1 Å resolution cryo-EM structure of PHFs from the frontal cortex of an individual with sporadic Alzheimer’s disease in complex with the PET ligand MK-6240. It represents the fourth cryo-EM structure of tau filaments in complex with a PET ligand. The compounds APN-1607 (Shi et al., 2021), flortaucipir (Shi et al., 2023), and GTP-1 (Merz et al., 2023) have been visualised previously. The binding mode of MK-6240, which stacks with full occupancy relative to the tau monomers, and with a tilted orientation with respect to the helical axis to allow optimal stacking of the aromatic compound, resembles that of GTP-1 binding to tau PHFs and of flortaucipir binding to CTE type I filaments. As also discussed in this paper, it remains unclear whether this binding mode is the same as the binding mode that is relevant to imaging in vivo. In this context, it is of note that similar experiments with flortaucipir, which is an FDA-approved PET ligand for tau inclusions of Alzheimer’s disease, did not reveal binding to PHFs. It is possible that the high concentration of PET ligands used in these studies could result in the visualisation of binding modes that are not relevant in vivo. The authors propose to address this question by directing future work toward solving structures using sub-stoichiometric conditions.

    References:

    Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SH, Goedert M. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. 2021 May;141(5):697-708. Epub 2021 Mar 16 PubMed. Correction.

    Shi Y, Ghetti B, Goedert M, Scheres SH. Cryo-EM Structures of Chronic Traumatic Encephalopathy Tau Filaments with PET Ligand Flortaucipir. J Mol Biol. 2023 Jun 1;435(11):168025. Epub 2023 Jun 16 PubMed.

    Merz GE, Chalkley MJ, Tan SK, Tse E, Lee J, Prusiner SB, Paras NA, DeGrado WF, Southworth DR. Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments. Nat Commun. 2023 May 26;14(1):3048. PubMed.

    View all comments by Michel Goedert

  2. Ligand-ligand interactions appear to dominate binding energetics at very high ligand concentrations, and are a consistent finding with cryo-EM studies of ligand-fibril interactions, such as those reported with MK-6240 and paired helical filaments (PHF) in this study. Still, it is important to note that significant radioligand-radioligand interactions at the high affinity PHF binding site are statistically unlikely at the concentrations employed in PET imaging studies, which are typically conducted at 20,000-fold lower ligand concentrations than utilized in this study i.e., <1 nM versus 20 μM used here. It is possible that the high-affinity, PET radioligand binding site for [18F]MK-6240 on PHF/neurofibrillary tangles is in the C-shaped cavity containing amino acids Q351-I360, but it is also possible that it resides in a location where ligand-ligand interactions are minimal, do not dominate, and would therefore not be detectable using cryo-EM.

    View all comments by Chester Mathis

  3. Together with a recent study that solved the structure of GTP1 in complex with tau PHFs from an AD brain sample (Merz et al., 2023), now we have the CryoEM structure for the AD tau PHF:MK6240 complex, which is also obtained with a 1:1 stoichiometry. We can see that the stacking of GTP1 and MK6240 both induce significant conformational change for the binding site, spanning from Q351 to I360. For example, the binding of GTP1 and MK6240 significantly enhanced the formation of the salt bridge between K353 and D358 compared to the apo AD tau PHFs (PDB 6HRE). These studies help people understand the special binding mode for GTP1 and MK6240 in AD tau PHFs and provide structural bases for further computational-based tracer design that can account for the aspects of dynamics, affinities, and kinetics.

    Note that both GTP1 and MK6240 are not so linear in shape compared to PBB3/PMPBB3 (APN1607). In a recent paper, the stacked binding mode was also observed for the linear F0502B, containing a medium aliphatic side chain, in α-synuclein fibrils (Xiang et al., 2023). However, the concentration of F0502B was much higher than GTP1 and MK6240. An intuition from these studies is that the more linear the tracer, the more unlikely it is to adopt the self-stacked binding mode. This assumption may be supported by the CroEM density map of APN1607 in AD tau fibrils (Shi et al., 2021). 

    References:

    Merz GE, Chalkley MJ, Tan SK, Tse E, Lee J, Prusiner SB, Paras NA, DeGrado WF, Southworth DR. Stacked binding of a PET ligand to Alzheimer's tau paired helical filaments. Nat Commun. 2023 May 26;14(1):3048. PubMed.

    Xiang J, Tao Y, Xia Y, Luo S, Zhao Q, Li B, Zhang X, Sun Y, Xia W, Zhang M, Kang SS, Ahn EH, Liu X, Xie F, Guan Y, Yang JJ, Bu L, Wu S, Wang X, Cao X, Liu C, Zhang Z, Li D, Ye K. Development of an α-synuclein positron emission tomography tracer for imaging synucleinopathies. Cell. 2023 Aug 3;186(16):3350-3367.e19. Epub 2023 Jul 7 PubMed.

    Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SH, Goedert M. Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607. Acta Neuropathol. 2021 May;141(5):697-708. Epub 2021 Mar 16 PubMed. Correction.

    View all comments by Junhaoi Li

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