4n6g

Tailoring Small Molecules for an Allosteric Site on Procaspase-6

spinqualitylabelsall models 4n6g, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4n6g is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 2GQ, PO4 Related: 4n5d, 4n7j, 4n7m, 4nbk, 4nbl, 4nbn Gene: CASP6, MCH2, procaspase-6 (HUMAN) Activity: Caspase-6, with EC number 3.4.22.59 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [CASP6_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. Publication Abstract from PubMed Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules. Tailoring Small Molecules for an Allosteric Site on Procaspase-6.,Murray J, Giannetti AM, Steffek M, Gibbons P, Hearn BR, Cohen F, Tam C, Pozniak C, Bravo B, Lewcock J, Jaishankar P, Ly CQ, Zhao X, Tang Y, Chugha P, Arkin MR, Flygare J, Renslo AR ChemMedChem. 2013 Nov 20. doi: 10.1002/cmdc.201300424. PMID:24259468 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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