Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design
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2010
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The ADP-ribosylating toxins (ADPRTs) and poly(ADP-ribose) polymerases (PARPs) are two important drug target protein families. Although the Y-X(10)-Y motif for the diphtheria toxin group and the STS motif for the other ADPRTs have been found to recognize the NAD(+) substrate, it is not known (i) if these two different motifs share any structural similarity, (ii) the key forces/residues contributing to NAD(+) binding, and (iii) if they recognize the same or different NAD(+) conformations. Here, we show that even though the different toxin groups and PARPs share insignificant sequence identity, they share a similar 3D structure shaped like a scorpion (the "scorpion" motif) whose first three and last residues interact mainly with the NAD(+) nicotinamide ring via van der Waals forces. This locally conserved structure binds the nicotinamide mononucleotide moiety in a structurally conserved ringlike conformation. The biological implications/applications of locally conserved structures for tox...ins/PARPs and the nicotinamide mononucleotide are discussed.
Izvor:
Journal of Medicinal Chemistry, 2010, 53, 10, 4038-4049Izdavač:
- Amer Chemical Soc, Washington
Finansiranje / projekti:
- NSC [NSC 95-2113-M-001-001]
- Human Frontiers Science Program
- Institute of Biomedical Sciences, Academia Sinica
DOI: 10.1021/jm1001106
ISSN: 0022-2623
PubMed: 20420408
WoS: 000277766900017
Scopus: 2-s2.0-77952684934
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Institucija/grupa
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Lee, Yu-Ming AU - Babu, C. Satheesan AU - Chen, Yao Chi AU - Milčić, Miloš K. AU - Qu, Yuanyuan AU - Lim, Carmay PY - 2010 UR - https://cherry.chem.bg.ac.rs/handle/123456789/1080 AB - The ADP-ribosylating toxins (ADPRTs) and poly(ADP-ribose) polymerases (PARPs) are two important drug target protein families. Although the Y-X(10)-Y motif for the diphtheria toxin group and the STS motif for the other ADPRTs have been found to recognize the NAD(+) substrate, it is not known (i) if these two different motifs share any structural similarity, (ii) the key forces/residues contributing to NAD(+) binding, and (iii) if they recognize the same or different NAD(+) conformations. Here, we show that even though the different toxin groups and PARPs share insignificant sequence identity, they share a similar 3D structure shaped like a scorpion (the "scorpion" motif) whose first three and last residues interact mainly with the NAD(+) nicotinamide ring via van der Waals forces. This locally conserved structure binds the nicotinamide mononucleotide moiety in a structurally conserved ringlike conformation. The biological implications/applications of locally conserved structures for toxins/PARPs and the nicotinamide mononucleotide are discussed. PB - Amer Chemical Soc, Washington T2 - Journal of Medicinal Chemistry T1 - Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design VL - 53 IS - 10 SP - 4038 EP - 4049 DO - 10.1021/jm1001106 ER -
@article{ author = "Lee, Yu-Ming and Babu, C. Satheesan and Chen, Yao Chi and Milčić, Miloš K. and Qu, Yuanyuan and Lim, Carmay", year = "2010", abstract = "The ADP-ribosylating toxins (ADPRTs) and poly(ADP-ribose) polymerases (PARPs) are two important drug target protein families. Although the Y-X(10)-Y motif for the diphtheria toxin group and the STS motif for the other ADPRTs have been found to recognize the NAD(+) substrate, it is not known (i) if these two different motifs share any structural similarity, (ii) the key forces/residues contributing to NAD(+) binding, and (iii) if they recognize the same or different NAD(+) conformations. Here, we show that even though the different toxin groups and PARPs share insignificant sequence identity, they share a similar 3D structure shaped like a scorpion (the "scorpion" motif) whose first three and last residues interact mainly with the NAD(+) nicotinamide ring via van der Waals forces. This locally conserved structure binds the nicotinamide mononucleotide moiety in a structurally conserved ringlike conformation. The biological implications/applications of locally conserved structures for toxins/PARPs and the nicotinamide mononucleotide are discussed.", publisher = "Amer Chemical Soc, Washington", journal = "Journal of Medicinal Chemistry", title = "Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design", volume = "53", number = "10", pages = "4038-4049", doi = "10.1021/jm1001106" }
Lee, Y., Babu, C. S., Chen, Y. C., Milčić, M. K., Qu, Y.,& Lim, C.. (2010). Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design. in Journal of Medicinal Chemistry Amer Chemical Soc, Washington., 53(10), 4038-4049. https://doi.org/10.1021/jm1001106
Lee Y, Babu CS, Chen YC, Milčić MK, Qu Y, Lim C. Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design. in Journal of Medicinal Chemistry. 2010;53(10):4038-4049. doi:10.1021/jm1001106 .
Lee, Yu-Ming, Babu, C. Satheesan, Chen, Yao Chi, Milčić, Miloš K., Qu, Yuanyuan, Lim, Carmay, "Conserved Structural Motif for Recognizing Nicotinamide Adenine Dinucleotide in Poly(ADP-ribose) Polymerases and ADP-Ribosylating Toxins: Implications for Structure-Based Drug Design" in Journal of Medicinal Chemistry, 53, no. 10 (2010):4038-4049, https://doi.org/10.1021/jm1001106 . .