Structural highlights
5nsd is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
|
| Ligands: | , , |
| Gene: | NAMPT, PBEF, PBEF1 (HUMAN) |
| Activity: | Nicotinamide phosphoribosyltransferase, with EC number 2.4.2.12 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[NAMPT_HUMAN] Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway (By similarity).
Publication Abstract from PubMed
Unraveling the mechanism of action and molecular target of small molecules remains a major challenge in drug discovery. While many cancer drugs target genetic vulnerabilities, loss-of-function screens fail to identify essential genes in drug mechanism of action. Here, we report CRISPRres, a CRISPR-Cas-based genetic screening approach to rapidly derive and identify drug resistance mutations in essential genes. It exploits the local genetic variation created by CRISPR-Cas-induced non-homologous end-joining (NHEJ) repair to generate a wide variety of functional in-frame mutations. Using large sgRNA tiling libraries and known drug-target pairs, we validate it as a target identification approach. We apply CRISPRres to the anticancer agent KPT-9274 and identify nicotinamide phosphoribosyltransferase (NAMPT) as its main target. These results present a powerful and simple genetic approach to create many protein variants that, in combination with positive selection, can be applied to reveal the cellular target of small-molecule inhibitors.
Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes.,Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, Daelemans D Nat Commun. 2018 Feb 5;9(1):502. doi: 10.1038/s41467-017-02349-8. PMID:29402884[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Neggers JE, Kwanten B, Dierckx T, Noguchi H, Voet A, Bral L, Minner K, Massant B, Kint N, Delforge M, Vercruysse T, Baloglu E, Senapedis W, Jacquemyn M, Daelemans D. Target identification of small molecules using large-scale CRISPR-Cas mutagenesis scanning of essential genes. Nat Commun. 2018 Feb 5;9(1):502. doi: 10.1038/s41467-017-02349-8. PMID:29402884 doi:http://dx.doi.org/10.1038/s41467-017-02349-8
