9OHM

Cryo-EM structure of bovine phosphodiesterase 6 bound to CB-5083

Summary for 9OHM

• Entry DOI: 10.2210/pdb9ohm/pdb
• EMDB information: 70500
• Descriptor: Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha, Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta, Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma, ... (7 entities in total)
• Functional Keywords: gaf domain, phosphohydrolase, g protein-coupled receptor signaling, signaling protein, cb-5083
• Biological source: Bos taurus (domestic cattle); More
• Total number of polymer chains: 4
• Total formula weight: 218976.68

Authors

Crawford, J.,Munuganti, R.,Leung, C.,Singh, K.,Gates, E.,Zhu, X.,Bally, M.,Dos Santos, N.,Sharifiaghdam, M.,Nosrati, Z.,Axerio-Cilies, P.,Berezuk, A.,Cholak, S.,Cameron, D.,Subramaniam, S. (deposition date: 2025-05-05, release date: 2026-05-27, Last modification date: 2026-07-22)

Primary citation

Crawford, J.,Munuganti, R.,Leung, C.,Singh, K.,Gates, E.,Zhu, X.,Bally, M.,Santos, N.D.,Sharifiaghdam, M.,Nosrati, Z.,Axerio-Cilies, P.,Berezuk, A.M.,Cholak, S.,Merk, A.,Cameron, D.R.,Subramaniam, S.
Cryo-EM-guided subtractive optimization of a novel VCP/p97 inhibitor.
Iucrj, 13:364-372, 2026

PubMed Abstract: We report the cryo-EM structure-guided discovery of GND-135, a novel small-molecule inhibitor of the VCP/p97 AAA ATPase that demonstrates efficient inhibition of VCP/p97 in biochemical, cellular, and pharmacokinetic assays and in a tumor efficacy mouse model of acute myeloid leukemia. Our approach overcomes the liability in the clinical-stage compound CB-5083 where Phase I studies showed off-target activity of CB-5083 for the enzyme PDE6. From the cryo-EM structural analysis of CB-5083 bound to PDE6 and VCP/p97, we identified critical ligand/protein interactions in both proteins and rationally designed a small molecule that retains key interactions necessary for VCP/p97 inhibition while eliminating PDE6 off-target activity. We refer to this approach as `subtractive optimization' because we are leveraging our ability to determine both on-target and off-target cryo-EM structures to guide the medicinal chemistry campaign to enable more targeted compound design. While this strategy is not possible in all cases, the use of cryo-EM to tune on-site binding while eliminating off-target binding could be a generally applicable strategy for informing molecular design and accelerating small-molecule drug discovery.

PubMed: 42329166
DOI: 10.1107/S2052252526004604

Experimental method

ELECTRON MICROSCOPY (2.72 Å)