4WVP

Crystal structure of an activity-based probe HNE complex

Summary for 4WVP

• Entry DOI: 10.2210/pdb4wvp/pdb
• Related PRD ID: PRD_002139
• Descriptor: 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)
• Functional Keywords: neutrophil elastase, acitivity-based probe, inhibitor, protease, complex, hne, hycosul, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 26429.16

Authors

Lechtenberg, B.C.,Kasperkiewicz, P.,Robinson, H.R.,Drag, M.,Riedl, S.J. (deposition date: 2014-11-06, release date: 2015-02-11, Last modification date: 2023-11-15)

Primary citation

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

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

Experimental method

X-RAY DIFFRACTION (1.63 Å)