8V58

Complex of murine cathepsin K with bound heparan sulfate 12mer

8V58 の概要

• エントリーDOI: 10.2210/pdb8v58/pdb
• 分子名称: Cathepsin K, beta-D-galactopyranose-(1-4)-alpha-D-mannopyranose-(1-4)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid-(1-4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose-(1-4)-2-O-sulfo-alpha-L-idopyranuronic acid, ... (6 entities in total)
• 機能のキーワード: complex, heparan sulfate, protease, collagenase, hydrolase
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 51638.97

構造登録者

Pedersen, L.C.,Xu, D.,Krahn, J.M. (登録日: 2023-11-30, 公開日: 2024-10-09)

主引用文献

Zhang, X.,Luo, Y.,Hao, H.,Krahn, J.M.,Su, G.,Dutcher, R.,Xu, Y.,Liu, J.,Pedersen, L.C.,Xu, D.
Heparan sulfate selectively inhibits the collagenase activity of cathepsin K.
Matrix Biol., 129:15-28, 2024

PubMed Abstract: Cathepsin K (CtsK) is a cysteine protease with potent collagenase activity. CtsK is highly expressed by bone-resorbing osteoclasts and plays an essential role in resorption of bone matrix. Although CtsK is known to bind heparan sulfate (HS), the structural details of the interaction, and how HS regulates the biological functions of CtsK, remains largely unknown. In this report, we discovered that HS is a multifaceted regulator of the structure and function of CtsK. Structurally, HS forms a highly stable complex with CtsK and induces its dimerization. Co-crystal structures of CtsK with bound HS oligosaccharides reveal the location of the HS binding site and suggest how HS may support dimerization. Functionally, HS plays a dual role in regulating the enzymatic activity of CtsK. While it preserves the peptidase activity of CtsK by stabilizing its active conformation, it inhibits the collagenase activity of CtsK in a sulfation level-dependent manner. These opposing effects can be explained by our finding that the HS binding site is remote from the active site, which allows HS to specifically inhibit the collagenase activity without affecting the peptidase activity. At last, we show that structurally defined HS oligosaccharides effectively block osteoclast resorption of bone in vitro without inhibiting osteoclast differentiation, which suggests that HS-based oligosaccharide might be explored as a new class of selective CtsK inhibitor for many diseases involving exaggerated bone resorption.

PubMed: 38548090
DOI: 10.1016/j.matbio.2024.03.005

実験手法

X-RAY DIFFRACTION (3.1 Å)