About

Objective

Render an illustration showing relationship between the molecular structure and function of lysergic acid diethylamide (LSD). I aimed to make the content engaging and readable for a lay audience.

UCSF Chimera was developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.

Target audience

Educated lay audience.

Process

1. Research, layout and composition

The biggest challenge in this project was designing a composition that would fit all the key steps in LSD action, from administration of the drug to the effects of receptor binding.

2. Rendering

An earlier version of the spread

References (annotated)

Ishchenko, A., Wacker, D., Kapoor, M., Zhang, A., Han, G. W., Basu, S., … Cherezov, V. (2017). Structural insights into the extracellular recognition of the human serotonin 2B receptor by an antibody. Proceedings of the National Academy of Sciences, 114(31), 8223–8228. https://doi.org/10.1073/pnas.1700891114

• Duration of action of ecstasy.

Dasgupta, A. (2017). Challenges in Laboratory Detection of Unusual Substance Abuse: Issues with Magic Mushroom, Peyote Cactus, Khat, and Solvent Abuse. Advances in Clinical Chemistry (1st ed., Vol. 78). Elsevier Inc. https://doi.org/10.1016/bs.acc.2016.07.004

• Duration of psilocybin activity.

Kang, Y., Zhou, X. E., Gao, X., He, Y., Liu, W., Ishchenko, A., … Xu, H. E. (2015). Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature, 523(7562), 561–567. https://doi.org/10.1038/nature14656

• Used to inform the structure of arrestin that I should depict.

Passie, T., Halpern, J. H., Stichtenoth, D. O., Emrich, H. M., Hintzen, A. (2008). The pharmacology of lysergic acid diethylamide: A review. CNS Neuroscience & Therapeutics, 14(4). https://doi.org/10.1111/j.1755-5949.2008.00059.x

• Average duration of LSD activity.

PDB ID: 1CF1 – Bovine inactive arrestin

• Not human but so far the most appropriate structure I could find, used in Kang et al., 2015 and Scheerer & Sommer, 2017

PDB ID: 5MAM – Human insulin in complex with serotonin

• Used to obtain 3D structure of serotonin.

PDB ID: 5TVN – Human LSD-bound 5-HT2BR (Wacker et al., 2017)

• Used directly in illustration as secondary structure and surface structure model, close-up of binding pocket with LSD interacting with specific residues, 3D structure of LSD.

• Removed cytochrome b562 (UniProt P0ABE7) and rebuilt missing loop with (UniProt P41595).

• Orientation in the membrane from Orientations of Proteins in Membranes Database.

Quibell, R., Prommer, E. E., Mihalyo, M., Twycross, R., & Wilcock, A. (2011). Ketamine*. Journal of Pain and Symptom Management, 41(3), 640–649. https://doi.org/10.1016/j.jpainsymman.2011.01.001

• Duration of ketamine activity.

Scheerer, P., & Sommer, M. E. (2017). Structural mechanism of arrestin activation. Current Opinion in Structural Biology, 45, 160–169. https://doi.org/10.1016/j.sbi.2017.05.001

• Used to inform structure of arrestin to use/approximately how the protein should probably approach my receptor (see Kang et al., 2015).

UCSF Chimera--a visualization system for exploratory research and analysis. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. J Comput Chem.2004 Oct;25(13):1605-12.

• Program used for molecular structure visualizations: stick models and surface models for activated 5-HT2BR, and reference for 3D structure of receptors rendered in Adobe Photoshop.

Wacker, D., Wang, C., Katritch, V., Han, G. W., Huang, X.-P., Vardy, E., McCorvy, J. D., Jiang, Y., Chu, M., Siu, F. Y., Liu, W., Xu, H. E., Cherezov, V.. Roth, B. L., Stevens, R. C. (2013). Structural Features for Functional Selectivity at Serotonin Receptors. Science, 340(6132), 615–619. https://doi.org/10.1126/science.1232808

• Detailed explanation of conformational characteristics in LSD/5-HT2BR likely related to biased arrestin signalling (these are better summarized visually in Wacker et al., 2017).

Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., Lansu, K., Schools, Z. L., Che, T., Nichols, D. E., Shoichet, B. K., Dror, R. O. Roth, B. L. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3), 377–389.e12. https://doi.org/10.1016/j.cell.2016.12.033

• Main source for this illustration on the LSD/5-HT2BR structure-function relationship, specific LSD conformation most likely responsible for long residence time.

• Adopted similar visualization strategies for the receptor-ligand complex (secondary structure overview); close-up of orthosteric binding site; surface model of receptor with EL2 “lid”; close-up of motifs/conformational changes associated with biased signalling.

• Describes rotation of LSD at diethylamide when binding.

• Confirms that 5-HT2BR is a good model for 5-HT2AR (no crystal model for the latter yet).