6VUA

X-ray structure of human CD38 catalytic domain with 2'-Cl-araNAD+

Summary for 6VUA

• Entry DOI: 10.2210/pdb6vua/pdb
• Descriptor: ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase 1, [[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methoxy-oxidanyl-phosphoryl] [(2~{R},3~{R},4~{R})-4-chloranyl-3-oxidanyl-oxolan-2-yl]methyl hydrogen phosphate, POTASSIUM ION, ... (8 entities in total)
• Functional Keywords: inhibitor, cd38, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 61954.43

Authors

Dai, Z.,Zhang, X.N.,Nasertorabi, F.,Han, G.W.,Stevens, R.C.,Zhang, Y. (deposition date: 2020-02-14, release date: 2020-06-03, Last modification date: 2024-10-23)

Primary citation

Dai, Z.,Zhang, X.N.,Nasertorabi, F.,Cheng, Q.,Li, J.,Katz, B.B.,Smbatyan, G.,Pei, H.,Louie, S.G.,Lenz, H.J.,Stevens, R.C.,Zhang, Y.
Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases.
Sci Adv, 6:eaba6752-eaba6752, 2020

PubMed Abstract: Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate-ribosyl cyclase-enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.

PubMed: 32537509
DOI: 10.1126/sciadv.aba6752

Experimental method

X-RAY DIFFRACTION (1.5 Å)