Abstract
PSA interacts with at least two serine protease inhibitors (serpins): alpha‐1‐antichymotrypsin (ACT) and protein C inhibitor (PCI). Three‐dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X‐ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT‐PSA complex. PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 836-851 |
| Number of pages | 16 |
| Journal | Protein Science |
| Volume | 5 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1996 |
| MoE publication type | A1 Journal article-refereed |
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Structural investigation of the alpha-1-antichymotrypsin : Prostate-specific antigen complex by comparative model building. / Villoutreix, Bruno (Corresponding Author); Lilja, Hans; Pettersson, Kim; Lövgren, Timo; Teleman, Olle.
In: Protein Science, Vol. 5, No. 5, 1996, p. 836-851.Research output: Contribution to journal › Article › Scientific › peer-review
TY - JOUR
T1 - Structural investigation of the alpha-1-antichymotrypsin
T2 - Prostate-specific antigen complex by comparative model building
AU - Villoutreix, Bruno
AU - Lilja, Hans
AU - Pettersson, Kim
AU - Lövgren, Timo
AU - Teleman, Olle
N1 - Project code: B6SU00097
PY - 1996
Y1 - 1996
N2 - Prostate‐specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate‐derived member of which is human glandular kallikrein‐1 (hK2). Active PSA and hK2 are both 237‐residue kallikrein‐like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface‐accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2.PSA interacts with at least two serine protease inhibitors (serpins): alpha‐1‐antichymotrypsin (ACT) and protein C inhibitor (PCI). Three‐dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X‐ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT‐PSA complex. PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.
AB - Prostate‐specific antigen (PSA), produced by prostate cells, provides an excellent serum marker for prostate cancer. It belongs to the human kallikrein family of enzymes, a second prostate‐derived member of which is human glandular kallikrein‐1 (hK2). Active PSA and hK2 are both 237‐residue kallikrein‐like proteases, based on sequence homology. An hK2 model structure based on the serine protease fold is presented and compared to PSA and six other serine proteases in order to analyze in depth the role of the surface‐accessible loops surrounding the active site. The results show that PSA and hK2 share extensive structural similarity and that most amino acid replacements are centered on the loops surrounding the active site. Furthermore, the electrostatic potential surfaces are very similar for PSA and hK2.PSA interacts with at least two serine protease inhibitors (serpins): alpha‐1‐antichymotrypsin (ACT) and protein C inhibitor (PCI). Three‐dimensional model structures of the uncleaved ACT molecule were developed based upon the recent X‐ray structure of uncleaved antithrombin. The serpin was docked both to PSA and hK2. Amino acid replacements and electrostatic complementarities indicate that the overall orientation of the proteins in these complexes is reasonable. In order to investigate PSA's heparin interaction sites, electrostatic computations were carried out on PSA, hK2, protein C, ACT, and PCI. Two heparin binding sites are suggested on the PSA surface and could explain the enhanced complex formation between PSA and PCI, while inhibiting the formation of the ACT‐PSA complex. PSA, hK2, and their preliminary complexes with ACT should facilitate the understanding and prediction of structural and functional properties for these important proteins also with respect to prostate diseases.
U2 - 10.1002/pro.5560050505
DO - 10.1002/pro.5560050505
M3 - Article
VL - 5
SP - 836
EP - 851
JO - Protein Science
JF - Protein Science
SN - 0961-8368
IS - 5
ER -