Abstract:
:Previous reports describe modulators of X-linked inhibitor of apoptosis (XIAP)-caspase interaction designed from the AVPI N-terminal peptide sequence of second mitochondria-derived activator of caspase. A fragment-based drug design strategy was initiated to identify therapeutic non-peptidomimetic antagonists of X-linked inhibitor of apoptosis protein-protein interactions. Fragments that bind to the AVPI binding site of BIR3 (bacculoviral inhibitory repeat) were identified, and to further localize the fragment binding within the AVPI binding site, a point mutation was designed which alters the dynamics of flexible loops and blocks PI region of the binding cleft, thus enabling definition of weakly bound small molecules in the AV portion of the binding cleft. Nuclear magnetic resonance analysis confirmed the G306E mutation stabilizes the AV pocket. Biophysical characterization of the mutant confirms conformation change within the PI sub-pocket as evidenced by a significant diminishment in binding affinity of AVPI mimetics, yet the binding affinity of the smaller AV mimetics is maintained or slightly improved in the mutant compared with wild-type. Additional data from non-covalent mass spectrometry analysis shows enhanced binding of AV mimetics to the G306E mutant over the wild-type. The presented data outline a protein engineering strategy that allowed mapping of AV-replacements with better sensitivity and precision.
journal_name
Chem Biol Drug Desjournal_title
Chemical biology & drug designauthors
Moore CD,Wu H,Bolaños B,Bergqvist S,Brooun A,Pauly T,Nowlin Ddoi
10.1111/j.1747-0285.2009.00862.xsubject
Has Abstractpub_date
2009-09-01 00:00:00pages
212-23issue
3eissn
1747-0277issn
1747-0285pii
JPP862journal_volume
74pub_type
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