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TitleAn αIIbβ3 monoclonal antibody traps a semiextended conformation and allosterically inhibits large ligand binding.
Journal, issue, pagesBlood Adv, Vol. 8, Issue 16, Page 4398-4409, Year 2024
Publish dateAug 27, 2024
AuthorsLu Wang / Jialing Wang / Jihong Li / Thomas Walz / Barry S Coller /
PubMed AbstractMonoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet αIIbβ3. Protein disulfide isomerase (PDI) has been implicated in αIIbβ3 activation ...Monoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet αIIbβ3. Protein disulfide isomerase (PDI) has been implicated in αIIbβ3 activation and binds to thrombin-activated αIIbβ3. Using human platelets as the immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with thrombin receptor-activating peptide (T6). R21D10 also partially inhibited T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and adenosine 5'-diphosphate-induced platelet aggregation. Mutual competition experiments showed that R21D10 does not inhibit the binding of mAbs 10E5 (anti-αIIb cap domain) or 7E3 (anti-β3 β-I domain), and immunoblot studies indicated that R21D10 binds to β3. The dissociation of αIIbβ3 by EDTA had a minimal effect on R21D10 binding. Cryogenic electron microscopy of the αIIbβ3-R21D10 Fab complex revealed that R21D10 binds to the β3 integrin-epidermal growth factor 1 (I-EGF1) domain and traps an intermediate conformation of αIIbβ3 with semiextended leg domains. The binding of R21D10 produces a major structural change in the β3 I-EGF2 domain associated with a new interaction between the β3 I-EGF2 and αIIb thigh domains, which may prevent the swing-out motion of the β3 hybrid domain required for high-affinity ligand binding and protect αIIbβ3 from EDTA-induced dissociation. R21D10 partially reversed the ligand binding priming effect of eptifibatide, suggesting that it could convert the swung-out conformation into a semiextended conformation. We concluded that R21D10 inhibits ligand binding to αIIbβ3 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.
External linksBlood Adv / PubMed:38968144 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 4.4 Å
Structure data

43969

9axl

EMDB-43969, PDB-9axl:
Structure of the semi-extended AlphaIIbBeta3 in complex with R21D10 Fab
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-43983: The map of the bent AlphaIIbBeta3 in complex with R21D10 Fab
Method: EM (single particle) / Resolution: 4.4 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsBLOOD CLOTTING/IMMUNE SYSTEM / monoclonal antibody / integrin receptor / allosteric inhibitor / platelets / BLOOD CLOTTING / BLOOD CLOTTING-IMMUNE SYSTEM complex

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