1tw6
From Proteopedia
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'''Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac''' | '''Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac''' | ||
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[[Category: Vucic, D.]] | [[Category: Vucic, D.]] | ||
[[Category: Wallweber, H J.A.]] | [[Category: Wallweber, H J.A.]] | ||
| - | [[Category: | + | [[Category: Apoptosis inhibition]] |
| - | [[Category: | + | [[Category: Peptide complex]] |
| - | [[Category: | + | [[Category: Zinc binding]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 10:26:40 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 07:26, 3 May 2008
Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac
Overview
ML-IAP (melanoma inhibitor of apoptosis) is a potent anti-apoptotic protein that is strongly up-regulated in melanoma and confers protection against a variety of pro-apoptotic stimuli. The mechanism by which ML-IAP regulates apoptosis is unclear, although weak inhibition of caspases 3 and 9 has been reported. Here, the binding to and inhibition of caspase 9 by the single BIR (baculovirus IAP repeat) domain of ML-IAP has been investigated and found to be significantly less potent than the ubiquitously expressed XIAP (X-linked IAP). Engineering of the ML-IAP-BIR domain, based on comparisons with the third BIR domain of XIAP, resulted in a chimeric BIR domain that binds to and inhibits caspase 9 significantly better than either ML-IAP-BIR or XIAP-BIR3. Mutational analysis of the ML-IAP-BIR domain demonstrated that similar enhancements in caspase 9 affinity can be achieved with only three amino acid substitutions. However, none of these modifications affected binding of the ML-IAP-BIR domain to the IAP antagonist Smac (second mitochondrial activator of caspases). ML-IAP-BIR was found to bind mature Smac with low nanomolar affinity, similar to that of XIAP-BIR2-BIR3. Correspondingly, increased expression of ML-IAP results in formation of a ML-IAP-Smac complex and disruption of the endogenous interaction between XIAP and mature Smac. These results suggest that ML-IAP might regulate apoptosis by sequestering Smac and preventing it from antagonizing XIAP-mediated inhibition of caspases, rather than by direct inhibition of caspases.
About this Structure
1TW6 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP., Vucic D, Franklin MC, Wallweber HJ, Das K, Eckelman BP, Shin H, Elliott LO, Kadkhodayan S, Deshayes K, Salvesen GS, Fairbrother WJ, Biochem J. 2005 Jan 1;385(Pt 1):11-20. PMID:15485396 Page seeded by OCA on Sat May 3 10:26:40 2008
