# Structure and Function of Human Cytochrome P450 11B Enzymes Involved in Cushing’s Disease and Hypertension

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $170,921

## Abstract

Human blood pressure and stress/immune responses are controlled by the steroid
hormones aldosterone and cortisol, respectively. There are multiple disease states in
which these hormones are overproduced and for which selective inhibitors would be
clinically beneficial. However, the development of selective inhibitors of aldosterone
production by cytochrome P450 11B2 (CYP11B2) and cortisol production by cytochrome
P450 11B1 (CYP11B1) has been frustrated by their 93% amino acid sequence identity.
The current proposal seeks to rectify this gap in knowledge by determining structural
features of CYP11B1 that underlie functional differences from CYP11B2. The central
hypothesis is that structural and functional studies will reveal unique CYP11B1
characteristics that could be harnessed to support the design of isoform-selective drugs.
To probe differences in CYP11B enzyme interactions with ligands, we will determine Xray
structures of CYP11B1 with its substrate and several inhibitors that currently under
development but are non-optimal because of poor selectivity. Preliminary data suggests
structural differences compared to the existing corresponding CYP11B2 structure,
distinctions that might be exploited clinically (aim 1). Preliminary data also suggests that
the shared required redox partner adrenodoxin interacts differently with the two CYP11B
enzymes, which may provide an orthogonal approach to selective inhibition—one that
doesn’t focus on the active site. Thus an X-ray structure will also be determined for
CYP11B1 interacting with adrenodoxin by employing a fusion protein approach (aim 2).
The final aim probes different conformations of CYP11B1 that are likely to exist in
solution and in the membrane where this protein is normally embedded. All membrane
P450 structures have been determined by X-ray crystallography and packing
interactions occur via the membrane-binding surface through which ligands enter/exit.
Thus, while these proteins are known to be flexible and dynamic, X-ray crystallography
often only reveals one form, which may not be the most appropriate conformation for
inhibitor design. Application of cryo-EM to CYP11B1 (aim 3) is an orthogonal approach
to define more relevant conformations of this enzyme. Thus, the proposed research will
determine the structures and define new interactions controlling the activity of CYP11B1.
Contrasting this new information with CYP11B2 can subsequently be used to facilitate
the development of clinically-relevant molecules inhibitors specific for each enzyme.

## Key facts

- **NIH application ID:** 10599074
- **Project number:** 5R01GM135346-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Emily E Scott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $170,921
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599074

## Citation

> US National Institutes of Health, RePORTER application 10599074, Structure and Function of Human Cytochrome P450 11B Enzymes Involved in Cushing’s Disease and Hypertension (5R01GM135346-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10599074. Licensed CC0.

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