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J Biol Chem. 2019 Jan 25;294(4):1250-1256. doi: 10.1074/jbc.RA118.006840. Epub 2018 Nov 30.

Crystal structure of the complex between venom toxin and serum inhibitor from Viperidae snake.

Author information

1
From the Department of Chemistry, Faculty of Science, Fukuoka University, 19-1, 8-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan, anarumi@fukuoka-u.ac.jp.
2
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, and tadokorot@pharm.hokudai.ac.jp.
3
Radioisotope Center, Fukuoka University, Fukuoka 814-0180, Japan.
4
From the Department of Chemistry, Faculty of Science, Fukuoka University, 19-1, 8-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
5
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, and.
6
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan, and maenaka@pharm.hokudai.ac.jp.

Abstract

Venomous snakes have endogenous proteins that neutralize the toxicity of their venom components. We previously identified five small serum proteins (SSP-1-SSP-5) from a highly venomous snake belonging to the family Viperidae as inhibitors of various toxins from snake venom. The endogenous inhibitors belong to the prostate secretory protein of 94 amino acids (PSP94) family. SSP-2 interacts with triflin, which is a member of the cysteine-rich secretory protein (CRISP) family that blocks smooth muscle contraction. However, the structural basis for the interaction and the biological roles of these inhibitors are largely unknown. Here, we determined the crystal structure of the SSP-2-triflin complex at 2.3 Å resolution. A concave region centrally located in the N-terminal domain of triflin is fully occupied by the terminal β-strands of SSP-2. SSP-2 does not bind tightly to the C-terminal cysteine-rich domain of triflin; this domain is thought to be responsible for its channel-blocker function. Instead, the cysteine-rich domain is tilted 7.7° upon binding to SSP-2, and the inhibitor appears to sterically hinder triflin binding to calcium channels. These results help explain how an endogenous inhibitor prevents the venomous protein from maintaining homeostasis in the host. Furthermore, this interaction also sheds light on the binding interface between the human homologues PSP94 and CRISP-3, which are up-regulated in prostate and ovarian cancers.

KEYWORDS:

calcium channel; crystal structure; inhibitor; protein complex; serum; snake venom

PMID:
30504218
PMCID:
PMC6349104
DOI:
10.1074/jbc.RA118.006840
[Indexed for MEDLINE]

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