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PDBsum entry 4wvp
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Hydrolase/hydrolase inhibitor
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PDB id
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4wvp
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PDB id:
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| Name: |
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Hydrolase/hydrolase inhibitor
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Title:
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Crystal structure of an activity-based probe hne complex
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Structure:
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Neutrophil elastase. Chain: e. Synonym: bone marrow serine protease,elastase-2,human leukocyte elastase,hle,medullasin,pmn elastase. Btn-3v3-nlb-omt-oic-3v2. Chain: i. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
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Resolution:
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1.63Å
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R-factor:
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0.140
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R-free:
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0.169
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Authors:
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B.C.Lechtenberg,P.Kasperkiewicz,H.R.Robinson,M.Drag,S.J.Riedl
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Key ref:
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B.C.Lechtenberg
et al.
(2015).
The elastase-PK101 structure: mechanism of an ultrasensitive activity-based probe revealed.
Acs Chem Biol,
10,
945-951.
PubMed id:
DOI:
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Date:
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06-Nov-14
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Release date:
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11-Feb-15
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PROCHECK
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Headers
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References
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P08246
(ELNE_HUMAN) -
Neutrophil elastase from Homo sapiens
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Seq:
Struc:
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267 a.a.
218 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.21.37
- leukocyte elastase.
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Reaction:
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Hydrolysis of proteins, including elastin. Preferential cleavage: Val-|-Xaa > Ala-|-Xaa.
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DOI no:
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Acs Chem Biol
10:945-951
(2015)
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PubMed id:
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The elastase-PK101 structure: mechanism of an ultrasensitive activity-based probe revealed.
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B.C.Lechtenberg,
P.Kasperkiewicz,
H.Robinson,
M.Drag,
S.J.Riedl.
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ABSTRACT
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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.
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Links
