6SMA

Crystal structure of Human Neutrophil Elastase (HNE) in complex with the 3-Oxo-beta-Sultam inhibitor LMC249


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

3-Oxo-beta-sultam as a Sulfonylating Chemotype for Inhibition of Serine Hydrolases and Activity-Based Protein Profiling.

Carvalho, L.A.R.Almeida, V.T.Brito, J.A.Lum, K.M.Oliveira, T.F.Guedes, R.C.Goncalves, L.M.Lucas, S.D.Cravatt, B.F.Archer, M.Moreira, R.

(2020) ACS Chem Biol 15: 878-883

  • DOI: https://doi.org/10.1021/acschembio.0c00090
  • Primary Citation of Related Structures:  
    6QBU, 6QEN, 6QEO, 6SMA

  • PubMed Abstract: 

    3-Oxo-β-sultams are four-membered ring ambident electrophiles that can react with nucleophiles either at the carbonyl carbon or at the sulfonyl sulfur atoms, and that have been reported to inhibit serine hydrolases via acylation of the active-site serine residue. We have developed a panel of 3-oxo-β-sultam inhibitors and show, through crystallographic data, that they are regioselective sulfonylating electrophiles, covalently binding to the catalytic serine of human and porcine elastases through the sulfur atom. Application of 3-oxo-β-sultam-derived activity-based probes in a human proteome revealed their potential to label disease-related serine hydrolases and proteasome subunits. Activity-based protein profiling applications of 3-oxo-β-sultams should open up new opportunities to investigate these classes of enzymes in complex proteomes and expand the toolbox of available sulfur-based covalent protein modifiers in chemical biology.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmacia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Neutrophil elastase
A, B, C
218Homo sapiensMutation(s): 0 
Gene Names: ELANEELA2
EC: 3.4.21.37
UniProt & NIH Common Fund Data Resources
Find proteins for P08246 (Homo sapiens)
Explore P08246 
Go to UniProtKB:  P08246
PHAROS:  P08246
GTEx:  ENSG00000197561 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08246
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
D, E, F, H, I
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
LKK (Subject of Investigation/LOI)
Query on LKK

Download Ideal Coordinates CCD File 
O [auth C]3-[[1-[(4-bromophenyl)methyl]-1,2,3-triazol-4-yl]methylcarbamoyl]pentane-3-sulfonic acid
C16 H21 Br N4 O4 S
XOALJRIEKUWYNB-UHFFFAOYSA-N
BR
Query on BR

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth B],
M [auth C],
N [auth C]
BROMIDE ION
Br
CPELXLSAUQHCOX-UHFFFAOYSA-M
EDO
Query on EDO

Download Ideal Coordinates CCD File 
P [auth C],
Q [auth C]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.215 
  • R-Value Observed: 0.217 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 116.669α = 90
b = 105.913β = 121.072
c = 79.474γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
Aimlessdata scaling
PHASERphasing
Cootmodel building
BUSTER-TNTrefinement
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Fundacao para a Ciencia e a TecnologiaPortugalSAICTPAC/0019/2015
Fundacao para a Ciencia e a TecnologiaPortugalPTDC/BBB-BEP/2463/2014
Fundacao para a Ciencia e a TecnologiaPortugalPEst-OE/SAU/UI4013/2014
Fundacao para a Ciencia e a TecnologiaPortugalSFRH/BD/100400/2014
Fundacao para a Ciencia e a TecnologiaPortugalIF/00472/2014

Revision History  (Full details and data files)

  • Version 1.0: 2020-04-08
    Type: Initial release
  • Version 1.1: 2020-04-29
    Changes: Database references
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Advisory, Atomic model, Data collection, Derived calculations, Structure summary
  • Version 2.1: 2024-01-24
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary