5thp

Publication Abstract from PubMed

The collagen binding integrin alpha2beta1 plays a crucial role in hemostasis, fibrosis, and cancer progression amongst others. It is specifically inhibited by rhodocetin (RC), a C-type lectin-related protein (CLRP) found in Malayan pit viper (Calloselasma rhodostoma) venom. The structure of RC alone reveals a heterotetramer arranged as an alphabeta and gammadelta subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin alpha2 subunit, thereby blocking collagen-induced platelet aggregation. However, until now, the molecular basis for this interaction has remained unclear. Here, we present the molecular structure of the RCgammadelta-alpha2A complex solved to 3.0 A resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to alpha2beta1 integrin. Besides the release of the nonbinding RCalphabeta tandem, the RCgamma subunit interacts with loop 2 of the alpha2A domain as result of a dramatic conformational change. The RCdelta subunit contacts the integrin alpha2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked alpha2A domain mutants, point mutations within the alpha2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCgammadelta-alpha2A complex explains the inhibitory mechanism and specificity of RC for alpha2beta1 integrin.

Dramatic and concerted conformational changes enable rhodocetin to block alpha2beta1 integrin selectively.,Eble JA, McDougall M, Orriss GL, Niland S, Johanningmeier B, Pohlentz G, Meier M, Karrasch S, Estevao-Costa MI, Martins Lima A, Stetefeld J PLoS Biol. 2017 Jul 13;15(7):e2001492. doi: 10.1371/journal.pbio.2001492., eCollection 2017 Jul. PMID:28704364^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.