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4WVP

Crystal structure of an activity-based probe HNE complex

4WVP の概要
エントリーDOI10.2210/pdb4wvp/pdb
関連するBIRD辞書のPRD_IDPRD_002139
分子名称Neutrophil elastase, BTN-3V3-NLB-OMT-OIC-3V2, 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, ... (7 entities in total)
機能のキーワードneutrophil elastase, acitivity-based probe, inhibitor, protease, complex, hne, hycosul, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
由来する生物種Homo sapiens (Human)
詳細
タンパク質・核酸の鎖数2
化学式量合計26429.16
構造登録者
Lechtenberg, B.C.,Kasperkiewicz, P.,Robinson, H.R.,Drag, M.,Riedl, S.J. (登録日: 2014-11-06, 公開日: 2015-02-11, 最終更新日: 2023-11-15)
主引用文献Lechtenberg, B.C.,Kasperkiewicz, P.,Robinson, H.,Drag, M.,Riedl, S.J.
The Elastase-PK101 Structure: Mechanism of an Ultrasensitive Activity-based Probe Revealed.
Acs Chem.Biol., 10:945-951, 2015
Cited by
PubMed Abstract: Human neutrophil elastase (HNE) plays a central role in neutrophil host defense, but its broad specificity makes HNE a difficult target for both inhibitor and probe development. Recently, we identified the unnatural amino acid containing activity-based probe PK101, which exhibits astounding sensitivity and selectivity for HNE, yet completely lacks mechanistic explanation for its unique characteristics. Here, we present the crystal structure of the HNE-PK101 complex which not only reveals the basis for PK101 ultrasensitivity but also uncovers so far unrecognized HNE features. Strikingly, the Nle(O-Bzl) function in the P4 position of PK101 reveals and leverages an "exo-pocket" on HNE as a critical factor for selectivity. Furthermore, the PK101 P3 position harbors a methionine dioxide function, which mimics a post-translationally oxidized methionine residue and forms a critical hydrogen bond to the backbone amide of Gly219 of HNE. Gly219 resides in a Gly-Gly motif that is unique to HNE, yet compulsory for this interaction. Consequently, this feature enables HNE to accommodate substrates that have undergone methionine oxidation, which constitutes a hallmark post-translational modification of neutrophil signaling.
PubMed: 25581168
DOI: 10.1021/cb500909n
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.63 Å)
構造検証レポート
Validation report summary of 4wvp
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-16に公開中

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