Abstract 3396: Structural modeling and functional characterization of caspase inhibitor and tumor oncogene survivin 2B isoform: Implications in ligand binding and targeted drug design
Authors: Lee Eric H. , Chen Chen-Shing , Le Ly 
Published: August 2019

Survivin is a protein expressed in a variety of human tissues whose function is to inhibit apoptosis. It achieves this by indirectly blocking caspase 3- 7- and 9- activation, thereby retarding or preventing programmed cell death. Survivin has been found to be highly expressed and specific in cancer tissues, but is absent in terminally differentiated cells, thus making it an attractive drug target.

The structural basis through which survivin interacts with its neighboring proteins to inhibit apoptosis and promote cell growth is not well understood. Survivin is not believed to bind directly to caspases; instead, intermediary proteins such as XIAP, SMAC, and DIABLO are believed to first bind with survivin’s “BIR” domain and then bridge its binding to caspases.

Unfortunately at the present, small molecule inhibitors against wild-type survivin have not demonstrated consistent anti-tumor activity to reach viability. The recent discovery of functional splicing variants for survivin (exon insertions or deletions) has drawn focus into whether these isoforms confer increased tumor resilience or aggressiveness, and whether inhibitors should specifically be designed for these targets. Specifically, the deltaEx3 (exon3 frameshift), 2B (intron 2 ins. of 69bp), 2alpha (intron 2 197bp tail ins.), and 3B (intron 3 165bp ins.) splice isoforms have been correlated with poor prognosis in AML, astrocytoma, breast, lung, renal, colorectal, brain, thyroid, bladder, prostate, sarcoma, and ovarian cancer.

To date, no structural model, either crystal or NMR, has been elucidated for any of the survivin splice variants, nor has the full survivin molecule been solved in complex with its known ligands. We therefore employed a combination of homology modeling and molecular dynamics (MD) simulations to characterize and predict the three dimensional structure for the survivin’s most ubiquitous isoform, the 2B isomer, in which an alternative exon 2 termed “2B” includes a 69bp insertion. In addition, we characterized a model for survivin 2B complexed with SMAC/DIABLO, demonstrating for the first time in atomic level detail that the exon 2B insertion sequence plays a crucial role in stabilizing the survivin-SMAC/DIABLO interface involving both a hydrophobic interface protecting the binding pocket from solvent intrusion and also a conserved receptor-ligand network of stabilizing hydrogen bonds. By identifying the key residues and interactions on survivin’s BIR domain, we therefore can predict exposed regions which represent drug targets to competitively bind the BIR domain and prevent survivin 2B from initiating its functional cascade that inhibits apoptosis of malignant cells. The hypotheses generated from this study would naturally lend itself toward future high throughput studies for targeted small molecular inhibitors.

Citation Format: Eric H. Lee, Chen-Shing Chen, Ly Le. Structural modeling and functional characterization of caspase inhibitor and tumor oncogene survivin 2B isoform: Implications in ligand binding and targeted drug design [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3396.