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Crystal structure of Himalayan mistletoe RIP reveals the presence of a natural inhibitor and a new functionally active sugar-binding site
Structural highlights
FunctionML4_VISAL The A chain is responsible for inhibiting protein synthesis through the catalytic inactivation of 60S ribosomal subunits by removing adenine from position 4,324 of 28S rRNA. The B chain binds to cell receptors and probably facilitates the entry into the cell of the A chain; B chains are also responsible for cell agglutination (lectin activity). Inhibits growth of the human tumor cell line Molt4.[1] [2] [UniProtKB:P81446] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRibosome-inactivating proteins (RIPs) are toxins involved in plant defense. How the plant prevents autotoxicity is not yet fully understood. The present study is the first structural evidence of a naturally inhibited form of RIP from a plant. Himalayan mistletoe RIP (HmRIP) was purified from Viscum album leaves and crystallized with lactose. The structure was determined by the molecular replacement method and refined at 2.8-A resolution. The crystal structure revealed the presence of high quality non-protein electron density at the active site, into which a pteridine derivative (2-amino 4-isopropyl 6-carboxyl pteridine) was modeled. The carboxyl group of the ligand binds strongly with the key active site residue Arg(162), nullifies the positive charge required for catalysis, and thereby acts as a natural inhibitor. Lectin subunits of RIPs have two active sugar-binding sites present in 1alpha- and 2gamma-subdomains. A third functionally active site has been identified in the 1beta-subdomain of HmRIP. The 1beta-site is active despite the absence of conserved polar sugar-binding residues. Loss of these residues is compensated by the following: (i) the presence of an extended site where the penultimate sugar also interacts with the protein; (ii) the interactions of galactose with the protein main chain carbonyl and amide nitrogen atoms; (iii) the presence of a well defined pocket encircled by four walls; and (iv) a favorable stacking of the galactose ring with Tyr(66) besides the conserved Phe(75). The mode of sugar binding is also distinct at the 1alpha and 2gamma sugar-binding sites. Crystal structure of himalayan mistletoe ribosome-inactivating protein reveals the presence of a natural inhibitor and a new functionally active sugar-binding site.,Mishra V, Bilgrami S, Sharma RS, Kaur P, Yadav S, Krauspenhaar R, Betzel C, Voelter W, Babu CR, Singh TP J Biol Chem. 2005 May 27;280(21):20712-21. Epub 2005 Mar 17. PMID:15774467[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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