2ref
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(New page: 200px<br /><applet load="2ref" size="350" color="white" frame="true" align="right" spinBox="true" caption="2ref, resolution 2.750Å" /> '''Crystal structure o...)
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Revision as of 10:10, 23 January 2008
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Crystal structure of the loading GNATL domain of CurA from Lyngbya majuscula soaked with malonyl-CoA
Overview
An unexpected biochemical strategy for chain initiation is described for, the loading module of the polyketide synthase of curacin A, an anticancer, lead derived from the marine cyanobacterium Lyngbya majuscula. A central, GCN5-related N-acetyltransferase (GNAT) domain bears bifunctional, decarboxylase/S-acetyltransferase activity, both unprecedented for the, GNAT superfamily. A CurA loading tridomain, consisting of an adaptor, domain, the GNAT domain, and an acyl carrier protein, was assessed, biochemically, revealing that a domain showing homology to GNAT (GNAT(L)), catalyzes (i) decarboxylation of malonyl-coenzyme A (malonyl-CoA) to, acetyl-CoA and (ii) direct S-acetyl transfer from acetyl-CoA to load an, adjacent acyl carrier protein domain (ACP(L)). Moreover, the N-terminal, adapter domain was shown to facilitate acetyl-group transfer. Crystal, structures of GNAT(L) were solved at 1.95 angstroms (ligand-free form) and, 2.75 angstroms (acyl-CoA complex), showing distinct substrate tunnels for, acyl-CoA and holo-ACP(L) binding. Modeling and site-directed mutagenesis, experiments demonstrated that histidine-389 and threonine-355, at the, convergence of the CoA and ACP tunnels, participate in malonyl-CoA, decarboxylation but not in acetyl-group transfer. Decarboxylation precedes, acetyl-group transfer, leading to acetyl-ACP(L) as the key curacin A, starter unit.
About this Structure
2REF is a Single protein structure of sequence from Lyngbya majuscula with as ligand. Full crystallographic information is available from OCA.
Reference
GNAT-like strategy for polyketide chain initiation., Gu L, Geders TW, Wang B, Gerwick WH, Hakansson K, Smith JL, Sherman DH, Science. 2007 Nov 9;318(5852):970-4. PMID:17991863
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