한빛사 인터뷰
1. 논문관련 분야의 소개, 동향, 전망을 설명, 연구과정에서 생긴 에피소드
G protein-coupled receptors (GPCRs) are the largest group of transmembrane protein in the human genome and arguably the most successful group of pharmaceutical targets. Recent biophysical studies have shown that GPCRs are conformationally dynamic, and that agonists and G protein cooperatively promote an active conformation that leads to G protein activation and signaling. In contrast, inverse agonists promote an inactive receptor conformation that does not bind G protein and does not signal. In their unliganded basal state GPCRs generally favor an inactive conformation, although spontaneous adoption of active conformers can lead to constitutive signaling. As part of this conserved mechanism agonists promote receptor activation and the formation of transient active-state receptor-G protein complexes. Receptor-G protein complexes that form prior to agonist binding or receptor activation have also been described, but their properties and functional significance for signaling have remained largely unexplored.
This paper has demonstrated that preassociation of 5-HT7 serotonin receptors with Gs heterotrimers is necessary for agonist-induced signaling. While both inverse agonist and inactive receptor mutations both stabilize inactive-state 5HT7-Gs complexes, these complexes dissociate in response to agonists, allowing formation of conventional agonist-5HT7-Gs ternary complexes and subsequent Gs activation. This inactive state complex is critical for full dynamic range of agonist-induced signaling, as 5-HT7 receptors spontaneously activate Gs variants that cannot form inactive-state complexes. For 5-HT7 receptors two distinct receptor-G protein complexes, one conventional ternary complex and the other an inverse-coupled binary complex, are required for agonist induced signaling. The conclusions of this study for the first time provide a well-defined, functional role of preassembly in cellular signaling.
My experience with this project has provided me many exciting yet challenging moments. I am very thankful for the guidance and support I received from my mentor Dr. Nevin Lambert as well as our lab members and collaborators.
2. 연구를 진행했던 소속기관 또는 연구소에 대해 소개 부탁 드립니다.
As an MD/PhD student at the Medical College of Georgia at Augusta University, I joined the lab of Dr. Nevin Lambert where I have been exploring the role of GPCRs in cell signaling. The overall focus of the Lambert lab has been the cellular and molecular mechanisms of GPCR signaling, with particular emphasis on the role of GPCR-G protein complexes in initiating downstream signaling. Utilizing engineered probes for receptor and G protein activation, our approach employs a spectrum of biophysical assays including bioluminescence resonance energy transfer (BRET) and luciferase complementation, and imaging methods such as confocal and total internal reflection fluorescence microscopy (TIRF) to address our questions.
3. 연구활동 하시면서 평소 느끼신 점 또는 자부심, 보람
Throughout my research experience so far, discussion/exploring ideas with others has been one of the most exciting moments of science. Whether it is discussing your experimental result with your advisor or exchanging questions with colleagues/seniors at conferences, the shared moment of exploring the same question together imparts impressionable memories and new perspectives.
4. 이 분야로 진학하려는 후배들 또는 유학준비생들에게 도움이 되는 말씀을 해 주신다면?
I believe it is important for graduate students to have friends/peers they can connect to – in terms of both social life and science. Research can really be an isolating experience if you reserve your thoughts to yourself. Even if your colleagues are not in the same field, you never know how similar your experiences/hurdles can be.
5. 연구활동과 관련된 앞으로의 계획이 있으시다면?
The biggest remaining questions related to this paper are 1) what does this inverse coupled complex look like; 2) why does this mechanism exist; 3) is this a conserved mechanism that applies to other GPCRs? Recent advances in structural biology using cryo-EM, HDX-MS, DEER, computational modeling (and many more) have opened exciting avenues for understanding conventional GPCR-G protein interaction. I would love to understand the molecular details of the inverse-coupled 5-HT7-Gs complex.
6. 다른 하시고 싶은 이야기들....
Once again, I would like to express my gratitude to the members of the Lambert lab and our collaborators for helping to work out this interesting story. I also want to thank all those closest to me- I cannot express how invaluable your support, advice and understanding have been.
관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기