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Interrogation of Dynamic Proteins to Expand the Druggable Proteome.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Interrogation of Dynamic Proteins to Expand the Druggable Proteome./
作者:	Peiffer, Amanda Lee.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
面頁冊數:	160 p.
附註:	Source: Dissertations Abstracts International, Volume: 83-05, Section: B.
Contained By:	Dissertations Abstracts International83-05B.
標題:	Chemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28846663
ISBN:	9798471105348

Interrogation of Dynamic Proteins to Expand the Druggable Proteome.
Peiffer, Amanda Lee.

Interrogation of Dynamic Proteins to Expand the Druggable Proteome. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 160 p.

Source: Dissertations Abstracts International, Volume: 83-05, Section: B.

Thesis (Ph.D.)--University of Michigan, 2021.

This item must not be sold to any third party vendors.

The human proteome is vastly complex, and our understanding of it is constantly evolving. There are roughly 20,000 protein-coding genes in the human genome, yet only about 10% of the resultant proteins are deemed "druggable" targets. And, only half of those have disease relevance. Thus, the druggable proteome is surprisingly narrow, consisting largely of structured proteins with defined binding pockets. With so many disease signatures residing in the "undruggable" portion of the proteome, there is much work to be done to expand the druggable landscape. An area rich with disease relevance is dynamic protein-protein interactions (PPIs), which underpin many regulatory cellular functions both in healthy and diseased states. However, devoid of typical binding pockets that enable traditional drug discovery approaches (i.e. substrate mimicry), dynamic PPIs occur over large, flat surface areas, which is why they have remained "undrugged." A disproportionate number of dynamic proteins can be found in transcriptional regulation. As such, it provides an interesting avenue for chemical probe development and therapeutic intervention. For instance, a hallmark of cancerous cells are rampant growth and proliferation, with many proteins being overexpressed. While many research efforts have focused on targeting the overexpressed proteins themselves, halting the overexpression at the transcriptional level could stop the disease progression at its initiation. This dissertation works towards expanding the druggable proteome by establishing principles of molecular recognition that guide native PPIs. By primarily using molecular dynamics simulations, with complementary biophysical experimentation, I dissect coactivators and establish rules of activator recognition and engagement. In doing so, I demonstrate the utility of disorder in transcriptional regulation. In particular, I identify ways in which allostery manifests in dynamic coactivator proteins. Further, I explore how inhibition / enhancement of particular PPIs can be achieved using small molecules that attenuate fluctuations and disrupt binding allosterically.

ISBN: 9798471105348Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Protein dynamics

Interrogation of Dynamic Proteins to Expand the Druggable Proteome.
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