Insights into the activation mechanism of class I HDAC complexes by inositol phosphates.
Histone deacetylases (HDACs) 1, 2 and 3 form the catalytic subunit of several large transcriptional repression complexes. Unexpectedly, the enzymatic activity of HDACs in these complexes has been shown to be regulated by inositol phosphates, which bind in a pocket sandwiched between the HDAC and co-repressor proteins. However, the actual mechanism of activation remains poorly understood. Here we have elucidated the stereochemical requirements for binding and activation by inositol phosphates, demonstrating that activation requires three adjacent phosphate groups and that other positions on the inositol ring can tolerate bulky substituents. We also demonstrate that there is allosteric communication between the inositol-binding site and the active site. The crystal structure of the HDAC1:MTA1 complex bound to a novel peptide-based inhibitor and to inositol hexaphosphate suggests a molecular basis of substrate recognition, and an entropically driven allosteric mechanism of activation.
Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
Peter J
PJ
Watson
Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
Christopher J
CJ
Millard
Department of Pharmacy and Pharmacology, University of Bath BA2 7AY, UK.
Andrew M
0000-0001-9003-3540
AM
Riley
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK.
Naomi S
NS
Robertson
Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
Lyndsey C
LC
Wright
Department of Pharmacy and Pharmacology, University of Bath BA2 7AY, UK.
Himali Y
HY
Godage
Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
Shaun M
SM
Cowley
Department of Chemistry, University of Leicester, Leicester LE1 7RH, UK.
Andrew G
AG
Jamieson
Department of Pharmacy and Pharmacology, University of Bath BA2 7AY, UK.|Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.
Barry V L
BV
Potter
Henry Wellcome Laboratories of Structural Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, UK.
John W R
JW
Schwabe
D000494:Allosteric Regulation; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D000099186:Histone Deacetylase 3
D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D007295:Inositol Phosphates; D046912:Multiprotein Complexes; D000099186:Histone Deacetylase 3; C110550:HDAC1 protein, human