5THP

Rhodocetin in complex with the integrin alpha2-A domain

Summary for 5THP

• Entry DOI: 10.2210/pdb5thp/pdb
• Descriptor: Snaclec rhodocetin subunit gamma, Snaclec rhodocetin subunit delta, Integrin alpha-2, ... (9 entities in total)
• Functional Keywords: c-type lectin, integrin, venom, coagulation, cell adhesion
• Biological source: Homo sapiens (Human); More
• Cellular location: Secreted: D2YW39 D2YW40; Membrane; Single-pass type I membrane protein: P17301
• Total number of polymer chains: 18
• Total formula weight: 329928.14

Authors

McDougall, M.,Orriss, G.L.,Stetefeld, J. (deposition date: 2016-09-30, release date: 2017-08-02, Last modification date: 2024-10-23)

Primary citation

Eble, J.A.,McDougall, M.,Orriss, G.L.,Niland, S.,Johanningmeier, B.,Pohlentz, G.,Meier, M.,Karrasch, S.,Estevao-Costa, M.I.,Martins Lima, A.,Stetefeld, J.
Dramatic and concerted conformational changes enable rhodocetin to block alpha 2 beta 1 integrin selectively.
PLoS Biol., 15:e2001492-e2001492, 2017

PubMed Abstract: The collagen binding integrin α2β1 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 αβ and γδ subunit in a cruciform shape. RC specifically binds to the collagen binding A-domain of the integrin α2 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 RCγδ-α2A complex solved to 3.0 Å resolution. Our findings show that RC undergoes a dramatic structural reorganization upon binding to α2β1 integrin. Besides the release of the nonbinding RCαβ tandem, the RCγ subunit interacts with loop 2 of the α2A domain as result of a dramatic conformational change. The RCδ subunit contacts the integrin α2A domain in the "closed" conformation through its helix C. Combined with epitope-mapped antibodies, conformationally locked α2A domain mutants, point mutations within the α2A loop 2, and chemical modifications of the purified toxin protein, this molecular structure of RCγδ-α2A complex explains the inhibitory mechanism and specificity of RC for α2β1 integrin.

PubMed: 28704364
DOI: 10.1371/journal.pbio.2001492

Experimental method

X-RAY DIFFRACTION (3.006 Å)