5DL1

ClpP from Staphylococcus aureus in complex with AV145


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.253 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Reversible Inhibitors Arrest ClpP in a Defined Conformational State that Can Be Revoked by ClpX Association.

Pahl, A.Lakemeyer, M.Vielberg, M.T.Hackl, M.W.Vomacka, J.Korotkov, V.S.Stein, M.L.Fetzer, C.Lorenz-Baath, K.Richter, K.Waldmann, H.Groll, M.Sieber, S.A.

(2015) Angew Chem Int Ed Engl 54: 15892-15896

  • DOI: https://doi.org/10.1002/anie.201507266
  • Primary Citation of Related Structures:  
    5DL1

  • PubMed Abstract: 

    Caseinolytic protease P (ClpP) is an important regulator of Staphylococcus aureus pathogenesis. A high-throughput screening for inhibitors of ClpP peptidase activity led to the identification of the first non-covalent binder for this enzyme class. Co-crystallization of the small molecule with S. aureus ClpP revealed a novel binding mode: Because of the rotation of the conserved residue proline 125, ClpP is locked in a defined conformational state, which results in distortion of the catalytic triad and inhibition of the peptidase activity. Based on these structural insights, the molecule was optimized by rational design and virtual screening, resulting in derivatives exceeding the potency of previous ClpP inhibitors. Strikingly, the conformational lock is overturned by binding of ClpX, an associated chaperone that enables proteolysis by substrate unfolding in the ClpXP complex. Thus, regulation of inhibitor binding by associated chaperones is an unexpected mechanism important for ClpP drug development.


  • Organizational Affiliation

    Center for Integrated Protein Science at the Department of Chemistry, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
ATP-dependent Clp protease proteolytic subunit
A, B, C, D, E
A, B, C, D, E, F, G, H, I, J, K, L, M, N
195Staphylococcus aureusMutation(s): 0 
Gene Names: clpPSAB0722
EC: 3.4.21.92
UniProt
Find proteins for Q2G036 (Staphylococcus aureus (strain NCTC 8325 / PS 47))
Explore Q2G036 
Go to UniProtKB:  Q2G036
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ2G036
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5C2
Query on 5C2

Download Ideal Coordinates CCD File 
AA [auth M]
BA [auth N]
O [auth A]
P [auth B]
Q [auth C]
AA [auth M],
BA [auth N],
O [auth A],
P [auth B],
Q [auth C],
R [auth D],
S [auth E],
T [auth F],
U [auth G],
V [auth H],
W [auth I],
X [auth J],
Y [auth K],
Z [auth L]
1-(propan-2-yl)-N-{[2-(thiophen-2-yl)-1,3-oxazol-4-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-5-carboxamide
C18 H17 N5 O2 S
OISFTLSEOJZOQD-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.253 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 112.82α = 90
b = 97.75β = 95.49
c = 131.95γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
German Research FoundationGermanySFB1035

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-25
    Type: Initial release
  • Version 1.1: 2016-01-27
    Changes: Database references
  • Version 1.2: 2018-10-24
    Changes: Advisory, Author supporting evidence, Data collection, Derived calculations
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description