EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor.
ジャーナル・号・ページ	Nat Commun, Vol. 13, Issue 1, Page 6178, Year 2022
掲載日	2022年10月19日
著者	Charles Bayly-Jones / Christopher J Lupton / Claudia Fritz / Hariprasad Venugopal / Daniel Ramsbeck / Michael Wermann / Christian Jäger / Alex de Marco / Stephan Schilling / Dagmar Schlenzig / James C Whisstock /
PubMed 要旨	The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal ...The zinc-dependent metalloprotease meprin α is predominantly expressed in the brush border membrane of proximal tubules in the kidney and enterocytes in the small intestine and colon. In normal tissue homeostasis meprin α performs key roles in inflammation, immunity, and extracellular matrix remodelling. Dysregulated meprin α is associated with acute kidney injury, sepsis, urinary tract infection, metastatic colorectal carcinoma, and inflammatory bowel disease. Accordingly, meprin α is the target of drug discovery programs. In contrast to meprin β, meprin α is secreted into the extracellular space, whereupon it oligomerises to form giant assemblies and is the largest extracellular protease identified to date (~6 MDa). Here, using cryo-electron microscopy, we determine the high-resolution structure of the zymogen and mature form of meprin α, as well as the structure of the active form in complex with a prototype small molecule inhibitor and human fetuin-B. Our data reveal that meprin α forms a giant, flexible, left-handed helical assembly of roughly 22 nm in diameter. We find that oligomerisation improves proteolytic and thermal stability but does not impact substrate specificity or enzymatic activity. Furthermore, structural comparison with meprin β reveal unique features of the active site of meprin α, and helical assembly more broadly.
リンク	Nat Commun / PubMed:36261433 / PubMed Central
手法	EM (単粒子) / EM (サブトモグラム平均)
解像度	2.4 - 12.7 Å
構造データ	26419 7uab EMDB-26419: Human pro-meprin alpha (zymogen state)[subparticle localised reconstruction] PDB-7uab: Human pro-meprin alpha (zymogen state) 手法: EM (単粒子) / 解像度: 3.7 Å 26420 7uac EMDB-26420: Human pro-meprin alpha (zymogen state)[Focused classification and refinement] PDB-7uac: Human pro-meprin alpha (zymogen state) 手法: EM (単粒子) / 解像度: 2.7 Å EMDB-26421: Meprin alpha helix (activated) - full C1 consensus reconstruction 手法: EM (単粒子) / 解像度: 3.4 Å 26422 7uae EMDB-26422: Human meprin alpha (active state)[subparticle localised reconstruction] PDB-7uae: Human meprin alpha (active state) 手法: EM (単粒子) / 解像度: 2.6 Å 26423 7uaf EMDB-26423, PDB-7uaf: Human meprin alpha inhibitory complex with compound 10d (N~3~,N~3~-bis[(2H-1,3-benzodioxol-5-yl)methyl]-N-hydroxy-beta-alaninamide) 手法: EM (単粒子) / 解像度: 2.4 Å EMDB-26424: Meprin alpha helix in complex with fetuin-B [consensus C1 reconstruction] 手法: EM (単粒子) / 解像度: 3.7 Å 26426 7uai EMDB-26426: Meprin alpha helix in complex with fetuin-B [subparticle localised reconstruction, masked focused refinement] PDB-7uai: Meprin alpha helix in complex with fetuin-B 手法: EM (単粒子) / 解像度: 2.8 Å EMDB-27689: Sub-tomogram average of pro-meprin alpha supercoiled filament 手法: EM (サブトモグラム平均) / 解像度: 12.7 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン ChemComp-CA: Unknown entry / カルシウムジカチオン ChemComp-ZN: Unknown entry ChemComp-M6X: N~3~,N~3~-bis[(2H-1,3-benzodioxol-5-yl)methyl]-N-hydroxy-beta-alaninamide
由来	homo sapiens (ヒト) Homo sapeins (人工物)
キーワード	ONCOPROTEIN / Metalloprotease / complex / helical / extracellular