6MSL

Integrin AlphaVBeta3 ectodomain bound to EETI-II 2.5D

Summary for 6MSL

• Entry DOI: 10.2210/pdb6msl/pdb
• Related: 3IJE 4G1E 4G1M 4MMX 4MMY 4MMZ
• Descriptor: Integrin alpha-V, Integrin beta-3, Cystine Knot Protein 2.5D, ... (10 entities in total)
• Functional Keywords: hybrid domain, psi, egf repeats, beta tail, calf, thigh, beta propeller, rgd motif, fibronectin, vitronectin, cell adhesion
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 193657.95

Authors

van Agthoven, J.F.,Arnaout, M.A. (deposition date: 2018-10-16, release date: 2019-10-23, Last modification date: 2023-10-11)

Primary citation

Van Agthoven, J.F.,Shams, H.,Cochran, F.V.,Alonso, J.L.,Kintzing, J.R.,Garakani, K.,Adair, B.D.,Xiong, J.P.,Mofrad, M.R.K.,Cochran, J.R.,Arnaout, M.A.
Structural Basis of the Differential Binding of Engineered Knottins to Integrins alpha V beta 3 and alpha 5 beta 1.
Structure, 27:1443-1451.e6, 2019

PubMed Abstract: Targeting both integrins αVβ3 and α5β1 simultaneously appears to be more effective in cancer therapy than targeting each one alone. The structural requirements for bispecific binding of ligand to integrins have not been fully elucidated. RGD-containing knottin 2.5F binds selectively to αVβ3 and α5β1, whereas knottin 2.5D is αVβ3 specific. To elucidate the structural basis of this selectivity, we determined the structures of 2.5F and 2.5D as apo proteins and in complex with αVβ3, and compared their interactions with integrins using molecular dynamics simulations. These studies show that 2.5D engages αVβ3 by an induced fit, but conformational selection of a flexible RGD loop accounts for high-affinity selective binding of 2.5F to both integrins. The contrasting binding of the highly flexible low-affinity linear RGD peptides to multiple integrins suggests that a "Goldilocks zone" of conformational flexibility of the RGD loop in 2.5F underlies its selective binding promiscuity to integrins.

PubMed: 31353240
DOI: 10.1016/j.str.2019.06.011

Experimental method

X-RAY DIFFRACTION (3.104 Å)