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3MK8

The MCL-1 BH3 Helix is an Exclusive MCL-1 Inhibitor and Apoptosis Sensitizer

Summary for 3MK8
Entry DOI10.2210/pdb3mk8/pdb
DescriptorInduced myeloid leukemia cell differentiation protein Mcl-1 (3 entities in total)
Functional Keywordsmcl-1, mcl-1 sahb d, staple, sahb, bcl-2 family, apoptosis, anti-apoptotic, apoptosis-apoptosis regulator complex, apoptosis/apoptosis regulator
Biological sourceHomo sapiens (human)
Cellular locationMembrane ; Single-pass membrane protein : Q07820 Q07820
Total number of polymer chains2
Total formula weight20337.17
Authors
Stewart, M.,Fire, E.,Keating, A.E.,Walensky, L.D. (deposition date: 2010-04-14, release date: 2010-06-23, Last modification date: 2024-10-30)
Primary citationStewart, M.L.,Fire, E.,Keating, A.E.,Walensky, L.D.
The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer.
Nat.Chem.Biol., 6:595-601, 2010
Cited by
PubMed Abstract: The development of selective inhibitors for discrete anti-apoptotic BCL-2 family proteins implicated in pathologic cell survival remains a formidable but pressing challenge. Such precisely tailored compounds would serve as molecular probes and targeted therapies to study and treat human diseases driven by specific anti-apoptotic blockades. In particular, MCL-1 has emerged as a major resistance factor in human cancer. By screening a library of stabilized alpha-helix of BCL-2 domains (SAHBs), we determined that the MCL-1 BH3 helix is itself a potent and exclusive MCL-1 inhibitor. X-ray crystallography and mutagenesis studies defined key binding and specificity determinants, including the capacity to harness the hydrocarbon staple to optimize affinity while preserving selectivity. MCL-1 SAHB directly targets MCL-1, neutralizes its inhibitory interaction with pro-apoptotic BAK and sensitizes cancer cells to caspase-dependent apoptosis. By leveraging nature's solution to ligand selectivity, we generated an MCL-1-specific agent that defines the structural and functional features of targeted MCL-1 inhibition.
PubMed: 20562877
DOI: 10.1038/nchembio.391
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.321 Å)
Structure validation

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