8OY2

Human cyclin-dependent kinase 2 in complex with inhibitor HB-29260

Summary for 8OY2

• Entry DOI: 10.2210/pdb8oy2/pdb
• Descriptor: Cyclin-dependent kinase 2, (1S,2S,11aS)-1-methoxy-1,4,7,10-tetramethyl-2,9-bis(oxidanyl)-2,11a-dihydrobenzo[b][1,4]benzodioxepine-3,6-dione, GLYCEROL, ... (4 entities in total)
• Functional Keywords: inhibitor, kinase, cell cycle
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34545.06

Authors

Kordes, S.,Harvey, C.J.B. (deposition date: 2023-05-03, release date: 2023-11-29, Last modification date: 2023-12-06)

Primary citation

Dunbar, K.L.,Perlatti, B.,Liu, N.,Cornelius, A.,Mummau, D.,Chiang, Y.M.,Hon, L.,Nimavat, M.,Pallas, J.,Kordes, S.,Ng, H.L.,Harvey, C.J.B.
Resistance gene-guided genome mining reveals the roseopurpurins as inhibitors of cyclin-dependent kinases.
Proc.Natl.Acad.Sci.USA, 120:e2310522120-e2310522120, 2023

PubMed Abstract: With the significant increase in the availability of microbial genome sequences in recent years, resistance gene-guided genome mining has emerged as a powerful approach for identifying natural products with specific bioactivities. Here, we present the use of this approach to reveal the roseopurpurins as potent inhibitors of cyclin-dependent kinases (CDKs), a class of cell cycle regulators implicated in multiple cancers. We identified a biosynthetic gene cluster (BGC) with a putative resistance gene with homology to human CDK2. Using targeted gene disruption and transcription factor overexpression in , and heterologous expression of the BGC in we demonstrated that roseopurpurin C () is produced by this cluster and characterized its biosynthesis. We determined the potency, specificity, and mechanism of action of as well as multiple intermediates and shunt products produced from the BGC. We show that inhibits human CDK2 with a of 44 nM, demonstrates selectivity for clinically relevant members of the CDK family, and induces G1 cell cycle arrest in HCT116 cells. Structural analysis of complexed with CDK2 revealed the molecular basis of ATP-competitive inhibition.

PubMed: 37983497
DOI: 10.1073/pnas.2310522120

Experimental method

X-RAY DIFFRACTION (2.618 Å)