1TW6

Structure of an ML-IAP/XIAP chimera bound to a 9mer peptide derived from Smac

Summary for 1TW6

• Entry DOI: 10.2210/pdb1tw6/pdb
• Related: 1NW9 1OXN 1OXQ 1OY7
• Descriptor: Baculoviral IAP repeat-containing protein 7, Diablo homolog, mitochondrial, ZINC ION, ... (7 entities in total)
• Functional Keywords: zinc binding, peptide complex, apoptosis inhibition, inhibitor-apoptosis complex, inhibitor/apoptosis
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q96CA5; Mitochondrion: Q9NR28
• Total number of polymer chains: 4
• Total formula weight: 32280.51

Authors

Franklin, M.C.,Vucic, D.,Wallweber, H.J.A.,Das, K.,Shin, H.,Elliott, L.O.,Kadkhodayan, S.,Deshayes, K.,Salvesen, G.S.,Fairbrother, W.J. (deposition date: 2004-06-30, release date: 2004-11-02, Last modification date: 2023-08-23)

Primary citation

Vucic, D.,Franklin, M.C.,Wallweber, H.J.A.,Das, K.,Eckelman, B.P.,Shin, H.,Elliott, L.O.,Kadkhodayan, S.,Deshayes, K.,Salvesen, G.S.,Fairbrother, W.J.
Engineering ML-IAP to produce an extraordinarily potent caspase 9 inhibitor: implications for Smac-dependent anti-apoptotic activity of ML-IAP
Biochem.J., 385:11-20, 2005

PubMed Abstract: 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.

PubMed: 15485396
DOI: 10.1042/BJ20041108

Experimental method

X-RAY DIFFRACTION (1.713 Å)