Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2022 Feb 17;12:2691. doi: 10.1038/s41598-022-06591-z

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

PMC Copyright notice

Binding poses of spermidine predicted by multistep induced-fit docking. (a) Surface of vestibular binding pocket 1 centered around D281^6.58, vestibular binding pocket 2 centered around E294^7.36 and the orthosteric binding pocket centered around D112^3.32 from side view (upper) and top view (lower). (b) Positions of spermidine docked into TAAR9 through multi-step docking. Spermidine can be docked into two vestibular binding pockets and the orthosteric binding pocket described in (a). (c) Spermidine forms non-covalent bonds with residues in the orthosteric binding pocket and is stabilized by surrounding aromatic rings. The critical binding site, D112^3.32, forms salt bridges and hydrogen bonds with two amino groups of spermidine. Residues within 5 Å around spermidine were demonstrated. A relatively large proportion of amino acids have the structure of aromatic rings, forming an aromatic cage to stabilize the binding of spermidine. (d) Spermidine can be docked into vestibular binding pocket 1, forming salt bridge with D281^6.58. Side chains of Q191^45.51 in ECL2, Y293^7.35, E294^7.36, and backbones of A192^45.52 in ECL2, T288 in ECL3 also interact with spermidine. 16 residues within 5 Å range of spermidine are demonstrated. Among them, only 2 have aromatic rings. (e) Key residue of vestibular binding pocket 1, D281^6.58 was mutated to E with altered side chain length but preserved negative charge, and N with similar side chain length but eliminated negative charge. Dose-dependent response curves of WT, D281^6.58E, and D281^6.58N mutants show that mutation of D281^6.58 gives rise to lower receptor responses. (f) Spermidine can be docked into vestibular binding pocket 2. Two amino groups of spermidine can interact with E294^7.36 through salt bridge and hydrogen bond. In addition, side chain of S93^2.65 can also form hydrogen bond with spermidine. Backbones of three residues including S96^2.68, G188 in ECL2, and Q191^45.51 in ECL2 are observed to bind to spermidine in the other terminal. Likewise, residues within 5 Å range of spermidine are demonstrated and only three of them have aromatic rings. (g) Mutation of E294^7.36 to D leads to a significant decrease in receptor activity. Mutation of E294^7.36 to Q almost eliminates receptor response to spermidine.