Journal
JOURNAL OF STRUCTURAL BIOLOGY
Volume 206, Issue 2, Pages 170-182Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jsb.2019.03.001
Keywords
Serine protease; Plasma kallikrein; Small molecule; Inhibition; Binding mode
Funding
- Sandler Foundation [MR-15 -328599]
- National Institutes of Health [GM105404, GM073210, GM082250, GM094625]
- National Science Foundation [1330685]
- Plexxikon Inc.
- M.D. Anderson Cancer Center
- US Department of Energy, Office of Basic Energy Sciences, through the Integrated Diffraction Analysis Technologies program - US Department of Energy Office of Biological and Environmental Research [DE-ACO2-05CH11231]
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1330685] Funding Source: National Science Foundation
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Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both fulllength and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the similar to 10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity.
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