Lukasz Lebioda | University of South Carolina (original) (raw)

Papers by Lukasz Lebioda

Chemischer Informationsdienst, Jan 22, 1985

The following versions of software and data (see references i ○) were used in the production of t... more The following versions of software and data (see references i ○) were used in the production of this report:

C8γ is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane at... more C8γ is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane attack complex of complement (MAC). C8γ is disulfide-linked to a C8R subunit that is noncovalently associated with a C8 chain. In the present study, the three-dimensional structure of recombinant C8γ was determined by X-ray diffraction to 1.2 Å resolution. The structure displays a typical lipocalin fold forming a calyx with a distinct binding pocket that is indicative of a ligand-binding function for C8γ. When compared to other lipocalins, the overall structure is most similar to neutrophil gelatinase associated lipocalin (NGAL), a protein released from granules of activated neutrophils. Notable differences include a much deeper binding pocket in C8γ as well as variation in the identity and position of residues lining the pocket. In C8γ, these residues allow ligand access to a large hydrophobic cavity at the base of the calyx, whereas corresponding residues in NGAL restrict access. This suggests the natural ligands for C8γ and NGAL are significantly different in size. Cys 40 in C8γ, which forms the disulfide bond to C8R, is located in a partially disordered loop (loop 1, residues 38-52) near the opening of the calyx. Access to the calyx may be regulated by movement of this loop in response to conformational changes in C8R during MAC formation.

Chemischer Informationsdienst, Jan 24, 1984

Acta crystallographica, Feb 1, 1980

A survey of 26 crystal structures of urea adducts has revealed that there are systematic features... more A survey of 26 crystal structures of urea adducts has revealed that there are systematic features in urea-cation bonding. It has been found that in complexes with monovalent cations urea coordinates to two cations. In complexes with divalent cations urea shows a preference to bond to onl~¢ one cation, in the plane of the molecule, with an M2+-C=O angle of about 130-140 ° , rather than along the dipole-moment direction. The preferred geometry is the same for transition-and non-transition-metal cations.

ChemInform, Oct 31, 1989

ChemInform Abstract Depending on the molar ratio of the reactants, the first stable complexes of ... more ChemInform Abstract Depending on the molar ratio of the reactants, the first stable complexes of Ga with the dihydridobis(pyrazolyl)borate ligand i.e. the compounds (III) and (IV) (96% yield), are obtained from GaCl3 (I) and the salt (II). Compound (III) (space group Cc, Z=4) represents a rare example of neutral five-coordinate Ga(III), especially with ligands containing N donor atoms.

Biochemistry, Feb 25, 2010

Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of about... more Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of about 27 amino acids which is not present in bacterial TSs. The extension, which is disordered in all reported crystal structures of TSs, has been considered to play a primary role in protein turnover but not in catalytic activity. In mammalian cells, the variant V3A has a half-life similar to that of wild type human TS (wt hTS) while V3T is much more stable; V3L, V3F and V3Y have half-lives approximately half of that for wt hTS. Catalytic turnover rates for most Val3 mutants are only slightly diminished, as expected. However, two mutants, V3L and V3F, have strongly compromised dUMP binding, with K m,app values increased by factors of 47 and 58, respectively. For V3L, this observation can be explained by stabilization of the inactive conformation of loop 181-197, which prevents substrate binding. In the crystal structure of V3L, electron density corresponding to a leucine residue is present in a position which stabilizes loop 181-197 in the inactive conformation. Since this density is not observed in other mutants and all other leucine residues are ordered in this structure, it is likely that this density represents Leu3. In the crystal structure of a binary complex V3F•FdUMP, the nucleotide is bound in an alternative mode to that proposed for the catalytic complex, indicating that the high K m,app value is caused not by stabilization of the inactive conformer but by substrate binding in a non-productive, inhibitory site. These observations show that the N-terminal extension affects the conformational state of the hTS catalytic region. Each of the mechanisms leading to the high K m,app values can be exploited to facilitate design of compounds acting as allosteric inhibitors of hTS.

Chemischer Informationsdienst, Jan 22, 1985

The following versions of software and data (see references i ○) were used in the production of t... more The following versions of software and data (see references i ○) were used in the production of this report:

C8γ is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane at... more C8γ is a 22-kDa subunit of human C8, which is one of five components of the cytolytic membrane attack complex of complement (MAC). C8γ is disulfide-linked to a C8R subunit that is noncovalently associated with a C8 chain. In the present study, the three-dimensional structure of recombinant C8γ was determined by X-ray diffraction to 1.2 Å resolution. The structure displays a typical lipocalin fold forming a calyx with a distinct binding pocket that is indicative of a ligand-binding function for C8γ. When compared to other lipocalins, the overall structure is most similar to neutrophil gelatinase associated lipocalin (NGAL), a protein released from granules of activated neutrophils. Notable differences include a much deeper binding pocket in C8γ as well as variation in the identity and position of residues lining the pocket. In C8γ, these residues allow ligand access to a large hydrophobic cavity at the base of the calyx, whereas corresponding residues in NGAL restrict access. This suggests the natural ligands for C8γ and NGAL are significantly different in size. Cys 40 in C8γ, which forms the disulfide bond to C8R, is located in a partially disordered loop (loop 1, residues 38-52) near the opening of the calyx. Access to the calyx may be regulated by movement of this loop in response to conformational changes in C8R during MAC formation.

Chemischer Informationsdienst, Jan 24, 1984

Acta crystallographica, Feb 1, 1980

A survey of 26 crystal structures of urea adducts has revealed that there are systematic features... more A survey of 26 crystal structures of urea adducts has revealed that there are systematic features in urea-cation bonding. It has been found that in complexes with monovalent cations urea coordinates to two cations. In complexes with divalent cations urea shows a preference to bond to onl~¢ one cation, in the plane of the molecule, with an M2+-C=O angle of about 130-140 ° , rather than along the dipole-moment direction. The preferred geometry is the same for transition-and non-transition-metal cations.

ChemInform, Oct 31, 1989

ChemInform Abstract Depending on the molar ratio of the reactants, the first stable complexes of ... more ChemInform Abstract Depending on the molar ratio of the reactants, the first stable complexes of Ga with the dihydridobis(pyrazolyl)borate ligand i.e. the compounds (III) and (IV) (96% yield), are obtained from GaCl3 (I) and the salt (II). Compound (III) (space group Cc, Z=4) represents a rare example of neutral five-coordinate Ga(III), especially with ligands containing N donor atoms.

Biochemistry, Feb 25, 2010

Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of about... more Human and other mammalian thymidylate synthase (TS) enzymes have an N-terminal extension of about 27 amino acids which is not present in bacterial TSs. The extension, which is disordered in all reported crystal structures of TSs, has been considered to play a primary role in protein turnover but not in catalytic activity. In mammalian cells, the variant V3A has a half-life similar to that of wild type human TS (wt hTS) while V3T is much more stable; V3L, V3F and V3Y have half-lives approximately half of that for wt hTS. Catalytic turnover rates for most Val3 mutants are only slightly diminished, as expected. However, two mutants, V3L and V3F, have strongly compromised dUMP binding, with K m,app values increased by factors of 47 and 58, respectively. For V3L, this observation can be explained by stabilization of the inactive conformation of loop 181-197, which prevents substrate binding. In the crystal structure of V3L, electron density corresponding to a leucine residue is present in a position which stabilizes loop 181-197 in the inactive conformation. Since this density is not observed in other mutants and all other leucine residues are ordered in this structure, it is likely that this density represents Leu3. In the crystal structure of a binary complex V3F•FdUMP, the nucleotide is bound in an alternative mode to that proposed for the catalytic complex, indicating that the high K m,app value is caused not by stabilization of the inactive conformer but by substrate binding in a non-productive, inhibitory site. These observations show that the N-terminal extension affects the conformational state of the hTS catalytic region. Each of the mechanisms leading to the high K m,app values can be exploited to facilitate design of compounds acting as allosteric inhibitors of hTS.