6BH8

Crystal structure of ZMPSTE24 in complex with phosphoramidon

Summary for 6BH8

• Entry DOI: 10.2210/pdb6bh8/pdb
• Related: 2YPT 4AW6 5SYT
• Related PRD ID: PRD_000638
• Descriptor: CAAX prenyl protease 1 homolog, ZINC ION, N-ALPHA-L-RHAMNOPYRANOSYLOXY(HYDROXYPHOSPHINYL)-L-LEUCYL-L-TRYPTOPHAN, ... (4 entities in total)
• Functional Keywords: integral membrane protein, zinc metalloprotease, inhibitor complex, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 113259.84

Authors

Goblirsch, B.R.,Arachea, B.T.,Wiener, M.C. (deposition date: 2017-10-30, release date: 2018-08-15, Last modification date: 2023-10-04)

Primary citation

Goblirsch, B.R.,Arachea, B.T.,Councell, D.J.,Wiener, M.C.
Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24.
Acta Crystallogr D Struct Biol, 74:739-747, 2018

PubMed Abstract: The integral membrane protein zinc metalloprotease ZMPSTE24 possesses a completely novel structure, comprising seven long kinked transmembrane helices that encircle a voluminous 14 000 Å cavity 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 IC values 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.

PubMed: 30082509
DOI: 10.1107/S2059798318003431

Experimental method

X-RAY DIFFRACTION (3.85 Å)