Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin

Abstract

Marine macrolide toxins of trisoxazole family target actin with high affinity and specificity and have promising pharmacological properties. We present X-ray structures of actin in complex with two members of this family, kabiramide C and jaspisamide A, at a resolution of 1.45 and 1.6 A, respectively. The structures reveal the absolute stereochemistry of these toxins and demonstrate that their trisoxazole ring interacts with actin subdomain 1 while the aliphatic side chain is inserted into the hydrophobic cavity between actin subdomains 1 and 3. The binding site is essentially the same as the one occupied by the actin-capping domain of the gelsolin superfamily of proteins. The structural evidence suggests that actin filament severing and capping by these toxins is also analogous to that of gelsolin. Consequently, these macrolides may be viewed as small molecule biomimetics of an entire class of actin-binding proteins.

Structures of microfilament destabilizing toxins bound to actin provide insight into toxin design and activity

“…RedA and C, and SphB occlude a large surface area on actin as was observed for the trisoxazole macrolides (16,17) and more recently swinholide A (SwiA) (18). Comparison of the surface buried by RedA, RedC, SphB, and KabC shows that the primary source of binding stability for all these macrolides is due to hydrophobic interactions (Table 2, which is published as supporting information on the PNAS web site), where 60% of this surface area is provided by the aliphatic tail even though it contains fewer atoms than the macrocyclic ring.…”

“…8, which is published as supporting information on the PNAS web site). Furthermore, the conformation of actin observed here is closely related to that seen in the trisoxazoleactin complexes (16,17), where, for example, the RMS differences between the C␣ atoms of actin with RedA and SphB relative to KabC are 0.61 Å and 0.59 Å, respectively. Thus, the focus in this paper is the similarities and differences in the interaction of the toxins with actin, rather than the structure of actin itself.…”

“…Actin used in the crystallizations and low-speed centrifugation assays was obtained from rabbit muscle acetone powder as described in ref. 16.…”

“…RedA and C, and SphB, G, and F were isolated from the sponge Reidispongia coerulea collected south of New Caledonia and extracted according to published protocols (6,7). Kabiramide C (KabC) and halichondramide (Hal) were provided as a generous gift by Junichi Tanaka (University of Ryukyus, Okinawa, Japan) (13,14,16). Ulapualide A (UlaA) was provided as a generous gift by the late Paul Scheuer (University of Hawaii, Honolulu) (11).…”

RETRACTED: Antimicrobial secondary metabolites from marine gastropod egg capsules and egg masses

“…Interactions made by the ring with the opposing actin subunit are colored in green and involve residues Gly23, Asp25, Ile341, Ile345, Ser348, and Leu349. Altogether, these residues compose the binding site of trisoxazole macrolides like Kabiramide C in their 1:1 complex with G-actin [14] .…”