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PDBsum entry 6pmd
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Hydrolase/antibiotic
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PDB id
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6pmd
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PDB id:
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| Name: |
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Hydrolase/antibiotic
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Title:
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Structure of clpp from staphylococcus aureus in complex with acyldepsipeptide
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Structure:
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Atp-dependent clp protease proteolytic subunit. Chain: a, b, c, d, e, f, g, i, k, l, m, n, s, t. Synonym: endopeptidase clp. Engineered: yes. Shv-wfp-ser-pro-ycp-ala-mp8 acyldepsipeptide. Chain: h, j, o, p, q, r, u, v, x, y, z. Engineered: yes
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Source:
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Staphylococcus aureus (strain nctc 8325). Organism_taxid: 93061. Strain: nctc 8325. Gene: clpp, saouhsc_00790. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
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Resolution:
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2.21Å
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R-factor:
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0.201
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R-free:
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0.227
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Authors:
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E.C.Griffith,R.E.Lee
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Key ref:
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E.C.Griffith
et al.
(2019).
Ureadepsipeptides as ClpP Activators.
ACS Infect Dis,
5,
1915-1925.
PubMed id:
DOI:
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Date:
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01-Jul-19
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Release date:
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06-Nov-19
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PROCHECK
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Headers
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References
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Q2G036
(CLPP_STAA8) -
ATP-dependent Clp protease proteolytic subunit from Staphylococcus aureus (strain NCTC 8325 / PS 47)
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Seq:
Struc:
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195 a.a.
184 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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Enzyme class:
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E.C.3.4.21.92
- endopeptidase Clp.
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Reaction:
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Hydrolysis of proteins to small peptides in the presence of ATP and magnesium. Alpha-casein is the usual test substrate. In the absence of ATP, only oligopeptides shorter than five residues are cleaved (such as succinyl-Leu-Tyr-|-NHMEC; and Leu-Tyr-Leu-|-Tyr-Trp, in which the cleavage of the -Tyr-|-Leu- and -Tyr-|-Trp- bond also occurs).
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DOI no:
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ACS Infect Dis
5:1915-1925
(2019)
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PubMed id:
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Ureadepsipeptides as ClpP Activators.
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E.C.Griffith,
Y.Zhao,
A.P.Singh,
B.P.Conlon,
R.Tangallapally,
W.R.Shadrick,
J.Liu,
M.J.Wallace,
L.Yang,
J.M.Elmore,
Y.Li,
Z.Zheng,
D.J.Miller,
M.N.Cheramie,
R.B.Lee,
M.D.LaFleur,
K.Lewis,
R.E.Lee.
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ABSTRACT
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Acyldepsipeptides are a unique class of antibiotics that act via allosterically
dysregulated activation of the bacterial caseinolytic protease (ClpP). The
ability of ClpP activators to kill nongrowing bacteria represents a new
opportunity to combat deep-seated biofilm infections. However, the
acyldepsipeptide scaffold is subject to rapid metabolism. Herein, we explore
alteration of the potentially metabolically reactive α,β unsaturated acyl
chain. Through targeted synthesis, a new class of phenyl urea substituted
depsipeptide ClpP activators with improved metabolic stability is described. The
ureadepsipeptides are potent activators of Staphylococcus aureus ClpP and
show activity against Gram-positive bacteria, including S. aureus
biofilms. These studies demonstrate that a phenyl urea motif can successfully
mimic the double bond, maintaining potency equivalent to acyldepsipeptides but
with decreased metabolic liability. Although removal of the double bond from
acyldepsipeptides generally has a significant negative impact on potency,
structural studies revealed that the phenyl ureadepsipeptides can retain potency
through the formation of a third hydrogen bond between the urea and the key
Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new
class of ClpP activators with improved drug-like properties, potent
antibacterial activity, and the tractability to be further optimized.
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