邓迪大学PhD position in China Scholarship Council: Charting the atlas and mechanistic structural features of small-molecule degraders that glue intrinsic protein-E3 ligase interactions申请条件要求-申请方
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邓迪大学
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About the Project
Targeted protein degradation (TPD) is a new modality of chemical tools and drugs that trigger depletion of a target protein inside the cell. Degraders work via forming a ternary complex with the target and a ubiquitin E3 ligase. This allows the E3 ligase to label the target protein for ubiquitination and subsequent degradation by the proteasome. Degraders are typically categorized as either bifunctional compounds (also known as proteolysis-targeting chimeras, or PROTACs) which are composed of two separate ligands that individually bind the target and E3 ligase; or molecular glues that typically bind monovalently either the ligase or the target1-3.
Together with Dr. Georg Winter (CEMM, Vienna), we have illuminated small-molecule degraders that intramolecularly bridge two protein domains in a target protein (BRD2 or BRD4) to nucleate proximity to either DCAF11 or DCAF16 E3 ligases (Hsia, Nature 2024)4. Using chemistry, orthogonal genetic screening, biophysical and cellular characterization, and structural biology, we investigate the mechanism of action of bifunctional BRD2/4 degraders (IBG1-4) and find that – instead of connecting target and ligase in trans as PROTACs are designed to do – they simultaneously engage and connect two adjacent domains of the target protein in cis. This conformational change glues BRD4 to the E3 ligases DCAF11 or DCAF16. Structural insights into the ternary BRD4:IBG1:DCAF16 complex guided the rational design of improved degraders of low picomolar potency (Figure 1).
In the course of this work, we made the exciting observation that DCAF11/16 ligases exhibit intrinsic binding affinities with BRD2/4. The degraders induce a conformation change on BRD2/4, to “glue” such intrinsic target-ligase affinity, that underpin its potent profound activity. This observation establishes an emerging concept5: that for molecular glue degraders to work, there must be a pre-existing interaction between an E3 and the neo-substrate. The interaction is however often low-affinity and functionally inconsequential – i.e. does not translate to target protein degradation in the absence of compound. This in turns prompt the enticing and compelling hypothesis that if we could pre-define which targets are “good” for each E3s, we could dramatically accelerate the way in which we can rationally design molecular glue degraders.
The project will develop and apply novel approaches, including chemical, biophysical and cellular methods, to identify and leverage weak-affinity protein-E3 interactions between recombinant proteins and/or endogenous proteins inside the cell. The project will have the support as second supervisor of Dr. Ron Hay, whose research group work on studying mechanisms of protein ubiquitination.
Our research community thrives on the diversity of students and staff which helps to make the University of Dundee a UK university of choice for postgraduate research.We welcome applications from all talented individuals and are committed to widening access to those who have the ability and potential to benefit from higher education.
邓迪大学Phd申请条件和要求都有哪些？PhD position in China Scholarship Council: Charting the atlas and mechanistic structural features of small-molecule degraders that glue intrinsic protein-E3 ligase interactions项目是不是全奖？有没有奖学金？下面我们一起看一下邓迪大学申请Phd直招需要具备哪些条件和要求，以及托福、雅思语言成绩要到多少才能申请。
申请要求
In order to be eligible for these awards applicants must:
be a Chinese national
meet the requirements of the CSC
hold an unconditional offer to study for a PhD at the University of Dundee and meet our English language requirements
have completed a bachelors or masters degree before the agreed start of PhD study
Already have an IELTS score of 6.5 at time of applying
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