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PDBsum entry 3ukr
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Structural protein
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PDB id
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3ukr
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Contents |
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401 a.a.
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193 a.a.
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349 a.a.
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282 a.a.
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173 a.a.
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167 a.a.
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136 a.a.
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PDB id:
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Structural protein
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Title:
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Crystal structure of bos taurus arp2/3 complex with bound inhibitor ck-666
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Structure:
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Actin-related protein 3. Chain: a. Synonym: actin-2, actin-like protein 3. Actin-related protein 2. Chain: b. Synonym: actin-like protein 2. Actin-related protein 2/3 complex subunit 1b. Chain: c. Synonym: arp2/3 complex 41 kda subunit, p41-arc.
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Source:
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Bos taurus. Bovine,cow,domestic cattle,domestic cow. Organism_taxid: 9913. Organism_taxid: 9913
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Resolution:
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2.48Å
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R-factor:
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0.221
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R-free:
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0.261
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Authors:
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B.J.Nolen,M.Han
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Key ref:
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A.W.Baggett
et al.
(2012).
Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.
Chemmedchem,
7,
1286-1294.
PubMed id:
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Date:
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09-Nov-11
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Release date:
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13-Feb-13
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PROCHECK
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Headers
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References
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P61157
(ARP3_BOVIN) -
Actin-related protein 3 from Bos taurus
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Seq:
Struc:
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418 a.a.
401 a.a.
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A7MB62
(ARP2_BOVIN) -
Actin-related protein 2 from Bos taurus
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Seq:
Struc:
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394 a.a.
193 a.a.
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Q58CQ2
(ARC1B_BOVIN) -
Actin-related protein 2/3 complex subunit 1B from Bos taurus
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Seq:
Struc:
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372 a.a.
349 a.a.
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Q3MHR7
(ARPC2_BOVIN) -
Actin-related protein 2/3 complex subunit 2 from Bos taurus
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Seq:
Struc:
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300 a.a.
282 a.a.
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Q3T035
(ARPC3_BOVIN) -
Actin-related protein 2/3 complex subunit 3 from Bos taurus
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Seq:
Struc:
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178 a.a.
173 a.a.
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Enzyme class:
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Chains A, B, C, D, E, F, G:
E.C.?
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Chemmedchem
7:1286-1294
(2012)
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PubMed id:
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Structural characterization and computer-aided optimization of a small-molecule inhibitor of the Arp2/3 complex, a key regulator of the actin cytoskeleton.
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A.W.Baggett,
Z.Cournia,
M.S.Han,
G.Patargias,
A.C.Glass,
S.Y.Liu,
B.J.Nolen.
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ABSTRACT
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CK-666 (1) is a recently discovered small-molecule inhibitor of the
actin-related protein 2/3 (Arp2/3) complex, a key actin cytoskeleton regulator
with roles in bacterial pathogenesis and cancer cell motility. Although 1 is
commercially available, the crystal structure of Arp2/3 complex with 1 bound has
not been reported, making its mechanism of action uncertain. Furthermore, its
relatively low potency increases its potential for off-target effects in vivo,
complicating interpretation of its influence in cell biological studies and
precluding its clinical use. Herein we report the crystal structure of 1 bound
to Arp2/3 complex, which reveals that 1 binds between the Arp2 and Arp3 subunits
to stabilize the inactive conformation of the complex. Based on the crystal
structure, we used computational docking and free-energy perturbation
calculations of monosubstituted derivatives of 1 to guide optimization efforts.
Biochemical assays of ten newly synthesized compounds led to the identification
of compound 2, which exhibits a threefold increase in inhibitory activity in
vitro relative to 1. In addition, our computational analyses unveiled a surface
groove at the interface of the Arp2 and Arp3 subunits that can be exploited for
additional structure-based optimization.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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J.D.Rotty,
C.Wu,
and
J.E.Bear
(2013).
New insights into the regulation and cellular functions of the ARP2/3 complex.
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Nat Rev Mol Cell Biol,
14,
7.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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