Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24

Goblirsch, Brandon R.; Arachea, Buenafe T.; Councell, Daniel J.; Wiener, Michael C.

doi:10.1107/S2059798318003431

Title: Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24

Journal Article · Tue Jul 24 00:00:00 EDT 2018 · Acta Crystallographica. Section D. Structural Biology

DOI:https://doi.org/10.1107/S2059798318003431· OSTI ID:1463719

Goblirsch, Brandon R.; Arachea, Buenafe T.; Councell, Daniel J.; Wiener, Michael C.

The integral membrane protein zinc metalloprotease ZMPSTE24 possesses a completely novel structure, comprising seven long kinked transmembrane helices that encircle a voluminous 14 000 Å³cavity within the membrane. Functionally conserved soluble zinc metalloprotease residues are contained within this cavity. As part of an effort to understand the structural and functional relationships between ZMPSTE24 and soluble zinc metalloproteases, the inhibition of ZMPSTE24 by phosphoramidon [N-(α-rhamnopyranosyl-oxyhydroxyphosphinyl)-Leu-Trp], a transition-state analog and competitive inhibitor of multiple soluble zinc metalloproteases, especially gluzincins, has been characterized functionally and structurally. The functional results, the determination of preliminary IC₅₀values by the use of an intramolecular quenched-fluorescence fluorogenic peptide assay, indicate that phosphoramidon inhibits ZMPSTE24 in a manner consistent with competitive inhibition. The structural results, a 3.85 Å resolution X-ray crystal structure of a ZMPSTE24–phosphoramidon complex, indicate that the overall binding mode observed between phosphoramidon and soluble gluzincins is conserved. Based on the structural data, a significantly lower potency than that observed for soluble gluzincins such as thermolysin and neprilysin is predicted. These results strongly suggest a close relationship between soluble gluzincins and the integral membrane protein zinc metalloprotease ZMPSTE24.

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Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: NCINIH

OSTI ID:: 1463719

Journal Information:: Acta Crystallographica. Section D. Structural Biology, Vol. 74, Issue 8; ISSN 2059-7983

Publisher:: IUCr

Country of Publication:: United States

Language:: ENGLISH

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