Structural insights into the dual-targeting mechanism of Nutlin-3

Journal Article · Fri Mar 30 00:00:00 EDT 2012 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2012.02.113· OSTI ID:22207780

Shin, Jae-Sun; Ha, Ji-Hyang ^[1]; He, Fahu; Muto, Yutaka ^[2]; Ryu, Kyoung-Seok ^[3]; Yoon, Ho Sup ^[4]; Kang, Sunghyun; Park, Sung Goo; Park, Byoung Chul ^[1]; Choi, Sang-Un ^[5]; Chi, Seung-Wook ^[1]

---

1. Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of)
2. RIKEN Systems and Structural Biology Center, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045 (Japan)
3. Division of Magnetic Resonance, Korea Basic Science Institute, Chungcheongbuk-Do 363-883 (Korea, Republic of)
4. Division of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637511 (Singapore)
5. Research Center for Drug Discovery Technology, Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon 305-600 (Korea, Republic of)

Highlights: Black-Right-Pointing-Pointer Universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. Black-Right-Pointing-Pointer Nutlin-3 binds to the BH3 peptide-binding grooves of Bcl-2 family proteins. Black-Right-Pointing-Pointer A conserved Bcl-X{sub L} binding mechanism of the Nutlin-3 and BH3-mimetic compounds. Black-Right-Pointing-Pointer A molecular basis for the transcription-independent apoptosis by Nutlin-3. Black-Right-Pointing-Pointer Structural insights into the dual-targeting mechanism of Nutlin-3. -- Abstract: Multi-targeting therapy is an emerging strategy of drug discovery to improve therapeutic efficacy, safety and resistance profiles. In this study, we monitored the binding of a potent MDM2 inhibitor Nutlin-3 with anti-apoptotic Bcl-2 family proteins using NMR spectroscopy. Our results showed the universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 family proteins. Taken together with the binding data for Nutlin-3 analogs, the structural model of the Bcl-X{sub L}/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-X{sub L}/Bcl-2 inhibitors, suggesting the molecular mechanism of transcription-independent mitochondrial apoptosis by Nutlin-3. Finally, our structural comparison provides structural insights into the dual-targeting mechanism of how Nutlin-3 can bind to two different target proteins, MDM2 and anti-apoptotic Bcl-2 family proteins in a similar manner.

• OSTI ID: 22207780
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 420; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
DRUGS
MITOCHONDRIA
NUCLEAR MAGNETIC RESONANCE
PEPTIDES
SPECTROSCOPY
STRUCTURAL MODELS
THERAPY
TRANSCRIPTION