7O86

1.73A X-ray crystal structure of the conserved C-terminal (CCT) of human SPAK

7O86 の概要

• エントリーDOI: 10.2210/pdb7o86/pdb
• 分子名称: STE20/SPS1-related proline-alanine-rich protein kinase, SODIUM ION, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: kinase, transferase, cct, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 23070.10

構造登録者

Elvers, K.T.,Bax, B.D.,Lipka-Lloyd, M.,Mehellou, Y. (登録日: 2021-04-14, 公開日: 2021-09-22, 最終更新日: 2024-01-31)

主引用文献

Elvers, K.T.,Lipka-Lloyd, M.,Trueman, R.C.,Bax, B.D.,Mehellou, Y.
Structures of the Human SPAK and OSR1 Conserved C-Terminal (CCT) Domains.
Chembiochem, 23:e202100441-e202100441, 2022

PubMed Abstract: STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress responsive 1 (OSR1) kinase are two serine/threonine protein kinases that regulate the function of ion co-transporters through phosphorylation. The highly conserved C-terminal (CCT) domains of SPAK and OSR1 bind to RFx[V/I] peptide sequences from their upstream 'With No Lysine Kinases (WNKs), facilitating their activation via phosphorylation. Thus, the inhibition of SPAK and OSR1 binding, via their CCT domains, to WNK kinases is a plausible strategy for inhibiting SPAK and OSR1 kinases. To facilitate structure-guided drug design of such inhibitors, we expressed and purified human SPAK and OSR1 CCT domains and solved their crystal structures. Interestingly, these crystal structures show a highly conserved primary pocket adjacent to a flexible secondary pocket. We also employed a biophysical strategy and determined the affinity of SPAK and OSR1 CCT domains to short peptides derived from WNK4 and NKCC1. Together, this work provides a platform that facilitates the design of CCT domain specific small molecule binders that inhibit SPAK- and OSR1-activation by WNK kinases, and these could be useful in treating hypertension and ischemic stroke.

PubMed: 34726826
DOI: 10.1002/cbic.202100441

実験手法

X-RAY DIFFRACTION (1.73 Å)