# Structure-function analysis and small molecule modulator discovery of human insulin degrading enzyme

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $368,974

## Abstract

Project Abstract/Summary:
Insulin degrading enzyme (IDE), an evolutionarily conserved metalloprotease, is involved in the
clearance of structurally diverse, bioactive peptides, e.g. three glucose regulating hormones (insulin,
amylin, and glucagon), amyloid β (Aβ), and CC chemokines. Accumulating evidence strongly supports
the role of IDE in the progression of several chronic human diseases including type 2 Diabetes Mellitus
and Alzheimer's disease. We have solved the structures of human IDE in the presence and absence of
diverse substrates. In conjunction with our biophysical and biochemical analyses, our studies reveal the
molecular basis of how IDE uses an enclosed catalytic chamber to selectively recognize the tertiary
structural features of their substrates to unfold and degrade them. Our long-term goals are to elucidate
the selective recognition of toxic peptides by IDE in proteostasis, delineate the normal and pathologic
functions of IDE, and develop small molecules that modulate IDE activity for treatment of various human
diseases such as type 2 diabetes and Alzheimer disease. Our objectives for this application are to gain
structural insights into the molecular dynamics of IDE and how the structural dynamics of IDE are linked
to their ability to recognize amyloid peptides. In addition, we will develop potent chemical modulators of
IDE to probe and modulate the biological functions of IDE. Our research rationale is that understanding
the regulation and functions of IDE as well as the development of small chemical modulators of IDE will
ultimately allow us to better design IDE-based therapy for the treatment of certain human diseases such
as diabetes, Alzheimer's disease, and inflammation. Three specific aims are proposed. In Aim 1, we will
integrate X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, cryo-electron
microscopy, small angle X-ray scattering, and molecular dynamic simulation to address the
conformational switches governing how IDE selectively degrades amyloid peptides that are diverse in
size and shape. Aim 2 is to analyze the link between IDE with type 2 diabetes using small molecule
inhibitors and IDE variants in type 2 diabetes patients. For Aim 3, we will discover small molecule
activators or activating mutations of IDE to enhance Aβ clearance as well as analyze the role of IDE in
the clearance of CCL3 and CCL4 in vivo. This work is significant because it will define structures of
multiple IDE open states, which are the key IDE conformational states for substrate recognition. Further,
this work will provide novel small molecule probes for manipulating IDE activity in vivo. Finally, the
studies will investigate the functional roles of IDE in human diseases. This work is innovative because
novel integrative structural approaches will be explored to examine the conformational changes of IDE
and novel small molecule discovery methods will be applied to identify new small molecule IDE inhibitors
and activators...

## Key facts

- **NIH application ID:** 9998965
- **Project number:** 5R01GM121964-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** WEI-JEN TANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,974
- **Award type:** 5
- **Project period:** 2017-09-01 → 2021-09-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998965

## Citation

> US National Institutes of Health, RePORTER application 9998965, Structure-function analysis and small molecule modulator discovery of human insulin degrading enzyme (5R01GM121964-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9998965. Licensed CC0.

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