Protein domain interfaces: characterization and comparison with oligomeric protein interfaces

Jones, Susan R.; Marin, Antoine; Thornton, Janet M.

doi:10.1093/protein/13.2.77

Cited by 143 publications

(133 citation statements)

References 25 publications

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“…A useful metric in the interface analysis of Jones et al is the gap volume index (26,28). This statistic, the ratio of the interface gap volume to the interface surface area, measures the fit between interacting surfaces, with smaller values indicating closer fits.…”

Section: Resultsmentioning

confidence: 99%

“…Models for methylcobalamin and cob(I)alamin were from the structures of the tryptic fragment (7) and the reactivation complex (18), respectively. Models were assessed by measuring the buried surface areas, the number and kinds of cobalamin-protein interactions, and the gap index, by using the Protein-Protein Interaction Server (www.biochem.ucl.ac.uk͞bsm͞PP͞server) (26) and CONTACTS from Collaborative Computational Project 4 (27). The properties of the domain interface were analyzed similarly.…”

Section: Models Of Bound Cobalamin and Analysis Of Interfacesmentioning

confidence: 99%

See 1 more Smart Citation

Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase

Evans

Huddler

Hilgers

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

140

146

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Section: Resultsmentioning

confidence: 99%

Section: Models Of Bound Cobalamin and Analysis Of Interfacesmentioning

confidence: 99%

Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase

Evans

Huddler

Hilgers

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

140

146

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“…The area buried at the interface is significantly larger than that of the HHP2-RNase, although its values ($720 Å 2 ) lies in the lower limit of the values usually needed to stabilize a dimeric form. 38 It should be noted, however, that at the serine rich hinge region interface several hydrogen bonds can be formed between the side chains of Ser17 of one subunit and Thr24 of the other, and vice versa, and between the OG atoms of the two Ser20 residues.…”

Section: Structure Of a Cytotoxic Dimeric Hp-rnase Variantmentioning

confidence: 99%

Structural features for the mechanism of antitumor action of a dimeric human pancreatic ribonuclease variant

et al. 2008

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A specialized class of RNases shows a high cytotoxicity toward tumor cell lines, which is critically dependent on their ability to reach the cytosol and to evade the action of the ribonuclease inhibitor (RI). The cytotoxicity and antitumor activity of bovine seminal ribonuclease (BSRNase), which exists in the native state as an equilibrium mixture of a swapped and an unswapped dimer, are peculiar properties of the swapped form. A dimeric variant (HHP2-RNase) of human pancreatic RNase, in which the enzyme has been engineered to reproduce the sequence of BSRNase helix-II (Gln28fiLeu, Arg31fiCys, Arg32fiCys, and Asn34fiLys) and to eliminate a negative charge on the surface (Glu111fiGly), is also extremely cytotoxic. Surprisingly, this activity is associated also to the unswapped form of the protein. The crystal structure reveals that on this molecule the hinge regions, which are highly disordered in the unswapped form of BSRNase, adopt a very well-defined conformation in both subunits. The results suggest that the two hinge peptides and the two Leu28 side chains may provide an anchorage to a transient noncovalent dimer, which maintains Cys31 and Cys32 of the two subunits in proximity, thus stabilizing a quaternary structure, similar to that found for the noncovalent swapped dimer of BSRNase, that allows the molecule to escape RI and/or to enhance the formation of the interchain disulfides.Keywords: crystal structure; antitumor agents; ribonuclease; 3D-domain swapping; dimers Abbreviations: BSRNase, bovine seminal ribonuclease; des(1-7)HP-RNase, human pancreatic ribonuclease in which the first seven residues have been deleted; HHP-RNase, covalent dimeric variant of human pancreatic ribonuclease in which four residues at the helix-II region are mutated according to BSRNase sequence (Gln28!Leu, Arg31!Cys, Arg32!Cys, and Asn34!Lys); HHP2-RNase, HHP-RNase with an additional mutation (Glu111!Gly); HP-RI, structure of human pancreatic ribonuclease complexed with ribonuclease inhibitor; HP-RNase, human pancreatic ribonuclease; MxM-BSRNase, dimeric form of BSRNase in which the chains swap their N-terminal tails; M¼M-BSRNase, unswapped dimer of BSRNase; M¼M-HHP2, unswapped dimer of HHP2-RNase; NCD-BSRNase, noncovalent swapped form of BSRNase; ONC, Onconase; PDB, Protein Data Bank; PM7, human pancreatic ribonuclease in which residues 1-21 are replaced by the corresponding residues of BSRNase; PM8, N-terminal swapped dimer of a variant of human pancreatic ribonuclease; RI, ribonuclease inhibitor; RMSD, root-mean-square deviation.Grant sponsor: Ministero dell'Istruzione, dell'Università e della Ricerca; Grant number: FIRB RBNE03B8KK and PRIN2007.

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“…2). The tetramer is stabilized by interactions between residues from the turn before A4, A4, B5, and B6 from each subunit, which result in the burial of 1,100-Å 2 surface area per subunit within the dimer of dimers interface (43,44). Further, the UPRT-uracil-cPRPP structure reveals interactions between the ␤-phosphate oxygen of cPRPP and residues Tyr-148 and Lys-150 from a third subunit that belongs to the ''other'' dimer (Fig.…”

Section: Substrate-assisted Catalysismentioning

confidence: 99%

The structural mechanism of GTP stabilized oligomerization and catalytic activation of the Toxoplasma gondii uracil phosphoribosyltransferase

Schumacher

Bashor

Song

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Uracil phosphoribosyltransferase (UPRT) is a member of a large family of salvage and biosynthetic enzymes, the phosphoribosyltransferases, and catalyzes the transfer of ribose 5-phosphate from ␣-D-5-phosphoribosyl-1-pyrophosphate (PRPP) to the N1 nitrogen of uracil. The UPRT from the opportunistic pathogen Toxoplasma gondii represents a promising target for rational drug design, because it can create intracellular, lethal nucleotides from subversive substrates. However, the development of such compounds requires a detailed understanding of the catalytic mechanism. Toward this end we determined the crystal structure of the T. gondii UPRT bound to uracil and cPRPP, a nonhydrolyzable PRPP analogue, to 2.5-Å resolution. The structure suggests that the catalytic mechanism is substrate-assisted, and a tetramer would be the more active oligomeric form of the enzyme. Subsequent biochemical studies revealed that GTP binding, which has been suggested to play a role in catalysis by other UPRTs, causes a 6-fold activation of the T. gondii enzyme and strikingly stabilizes the tetramer form. The basis for stabilization was revealed in the 2.45-Å resolution structure of the UPRT-GTP complex, whereby residues from three subunits contributed to GTP binding. Thus, our studies reveal an allosteric mechanism involving nucleotide stabilization of a more active, higher order oligomer. Such regulation of UPRT could play a role in the balance of purine and pyrimidine nucleotide pools in the cell.

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Protein domain interfaces: characterization and comparison with oligomeric protein interfaces

Cited by 143 publications

References 25 publications

Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase

Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase

Structural features for the mechanism of antitumor action of a dimeric human pancreatic ribonuclease variant

The structural mechanism of GTP stabilized oligomerization and catalytic activation of the Toxoplasma gondii uracil phosphoribosyltransferase

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