Structural investigation of the alpha-1-antichymotrypsin: Prostate-specific antigen complex by comparative model building

Bruno Villoutreix (Corresponding Author), Hans Lilja, Kim Pettersson, Timo Lövgren, Olle Teleman

Research output: Contribution to journalArticleScientificpeer-review

35 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)836-851
Number of pages16
JournalProtein Science
Volume5
Issue number5
DOIs
Publication statusPublished - 1996
MoE publication typeA1 Journal article-refereed

Fingerprint

alpha 1-Antichymotrypsin
Prostate-Specific Antigen
Antigens
Protein C Inhibitor
Static Electricity
Electrostatics
Serine Proteinase Inhibitors
Serine Proteases
Model structures
Heparin
Prostate
Catalytic Domain
Amino Acids
Kallikreins
Antithrombins
Surface Antigens
Sequence Homology
Protein C
Prostatic Neoplasms
Proteins

Cite this

Villoutreix, Bruno ; Lilja, Hans ; Pettersson, Kim ; Lövgren, Timo ; Teleman, Olle. / Structural investigation of the alpha-1-antichymotrypsin : Prostate-specific antigen complex by comparative model building. In: Protein Science. 1996 ; Vol. 5, No. 5. pp. 836-851.
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title = "Structural investigation of the alpha-1-antichymotrypsin: Prostate-specific antigen complex by comparative model building",
abstract = "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.",
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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 journalArticleScientificpeer-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.

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DO - 10.1002/pro.5560050505

M3 - Article

VL - 5

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EP - 851

JO - Protein Science

JF - Protein Science

SN - 0961-8368

IS - 5

ER -