7rdh

From Proteopedia

Crystal structure of the de novo designed binding protein H3mb in complex with the 1968 influenza A virus hemagglutinin

Structural highlights

7rdh is a 8 chain structure with sequence from Escherichia coli and Influenza A virus (A/Hong Kong/1/1968(H3N2)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.75Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

HEMA_I68A4 Binds to sialic acid-containing receptors on the cell surface, bringing about the attachment of the virus particle to the cell. This attachment induces virion internalization of about two third of the virus particles through clathrin-dependent endocytosis and about one third through a clathrin- and caveolin-independent pathway. Plays a major role in the determination of host range restriction and virulence. Class I viral fusion protein. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in HA2, releasing the fusion hydrophobic peptide. Several trimers are required to form a competent fusion pore (By similarity).

Publication Abstract from PubMed

The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains an outstanding challenge(1-5). We describe a general solution to this problem which starts with a broad exploration of the very large space of possible binding modes to a selected region of a protein surface, and then intensifies the search in the vicinity of the most promising binding modes. We demonstrate its very broad applicability by de novo design of binding proteins to 12 diverse protein targets with very different shapes and surface properties. Biophysical characterization shows that the binders, which are all smaller than 65 amino acids, are hyperstable and following experimental optimization bind their targets with nanomolar to picomolar affinities. We succeeded in solving crystal structures of five of the binder-target complexes, and all five are very close to the corresponding computational design models. Experimental data on nearly half a million computational designs and hundreds of thousands of point mutants provide detailed feedback on the strengths and limitations of the method and of our current understanding of protein-protein interactions, and should guide improvement of both. Our approach now enables targeted design of binders to sites of interest on a wide variety of proteins for therapeutic and diagnostic applications.

Design of protein binding proteins from target structure alone.,Cao L, Coventry B, Goreshnik I, Huang B, Park JS, Jude KM, Markovic I, Kadam RU, Verschueren KHG, Verstraete K, Walsh STR, Bennett N, Phal A, Yang A, Kozodoy L, DeWitt M, Picton L, Miller L, Strauch EM, DeBouver ND, Pires A, Bera AK, Halabiya S, Hammerson B, Yang W, Bernard S, Stewart L, Wilson IA, Ruohola-Baker H, Schlessinger J, Lee S, Savvides SN, Garcia KC, Baker D Nature. 2022 Mar 24. pii: 10.1038/s41586-022-04654-9. doi:, 10.1038/s41586-022-04654-9. PMID:35332283^[1]

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

References

↑ Cao L, Coventry B, Goreshnik I, Huang B, Park JS, Jude KM, Markovic I, Kadam RU, Verschueren KHG, Verstraete K, Walsh STR, Bennett N, Phal A, Yang A, Kozodoy L, DeWitt M, Picton L, Miller L, Strauch EM, DeBouver ND, Pires A, Bera AK, Halabiya S, Hammerson B, Yang W, Bernard S, Stewart L, Wilson IA, Ruohola-Baker H, Schlessinger J, Lee S, Savvides SN, Garcia KC, Baker D. Design of protein binding proteins from target structure alone. Nature. 2022 Mar 24. pii: 10.1038/s41586-022-04654-9. doi:, 10.1038/s41586-022-04654-9. PMID:35332283 doi:http://dx.doi.org/10.1038/s41586-022-04654-9