7r58 | pdb_00007r58
Crystal structure of the GPVI-glenzocimab complex
Structural highlights
DiseaseGPVI_HUMAN Bleeding diathesis due to glycoprotein VI deficiency. The disease is caused by mutations affecting the gene represented in this entry. FunctionGPVI_HUMAN Collagen receptor involved in collagen-induced platelet adhesion and activation. Plays a key role in platelet procoagulant activity and subsequent thrombin and fibrin formation. This procoagulant function may contribute to arterial and venous thrombus formation. The signaling pathway involves the FcR gamma-chain, the Src kinases (likely FYN or LYN) and SYK, the adapter protein LAT and leads to the activation of PLCG2.[1] [2] Publication Abstract from PubMedPlatelet glycoprotein VI (GPVI) is attracting interest as a potential target for the development of new antiplatelet molecules with a low bleeding risk. GPVI binding to vascular collagen initiates thrombus formation and GPVI interactions with fibrin promote the growth and stability of the thrombus. In this study, we show that glenzocimab, a clinical stage humanized antibody fragment (Fab) with a high affinity for GPVI, blocks the binding of both ligands through a combination of steric hindrance and structural change. A cocrystal of glenzocimab with an extracellular domain of monomeric GPVI was obtained and its structure determined to a resolution of 1.9 A. The data revealed that (1) glenzocimab binds to the D2 domain of GPVI, GPVI dimerization was not observed in the crystal structure because glenzocimab prevented D2 homotypic interactions and the formation of dimers that have a high affinity for collagen and fibrin; and (2) the light variable domain of the GPVI-bound Fab causes steric hindrance that is predicted to prevent the collagen-related peptide (CRP)/collagen fibers from extending out of their binding site and preclude GPVI clustering and downstream signaling. Glenzocimab did not bind to a truncated GPVI missing loop residues 129 to 136, thus validating the epitope identified in the crystal structure. Overall, these findings demonstrate that the binding of glenzocimab to the D2 domain of GPVI induces steric hindrance and structural modifications that drive the inhibition of GPVI interactions with its major ligands. Targeting platelet GPVI with glenzocimab: a novel mechanism for inhibition.,Billiald P, Slater A, Welin M, Clark JC, Loyau S, Pugniere M, Jiacomini IG, Rose N, Lebozec K, Toledano E, Francois D, Watson SP, Jandrot-Perrus M Blood Adv. 2023 Apr 11;7(7):1258-1268. doi: 10.1182/bloodadvances.2022007863. PMID:36375047[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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