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* Residue conservation analysis
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PDB id:
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Transcription
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Title:
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The vhl-elonginc-elonginb structure
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Structure:
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Protein (elongin b). Chain: a, d, g, j. Fragment: residues 1-120. Engineered: yes. Other_details: disordered residues: 99-120. Protein (elongin c). Chain: b, e, h, k. Fragment: residues 17-112. Engineered: yes.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Other_details: vhl(54-213) alternative endogenous polypeptide
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Biol. unit:
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Trimer (from
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Resolution:
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2.70Å
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R-factor:
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0.238
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R-free:
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0.289
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Authors:
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C.E.Stebbins,W.G.Kaelin,N.P.Pavletich
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Key ref:
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C.E.Stebbins
et al.
(1999).
Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.
Science,
284,
455-461.
PubMed id:
DOI:
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Date:
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13-Mar-99
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Release date:
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21-Apr-99
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PROCHECK
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Headers
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References
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Q15370
(ELOB_HUMAN) -
Elongin-B from Homo sapiens
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Seq:
Struc:
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118 a.a.
98 a.a.
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DOI no:
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Science
284:455-461
(1999)
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PubMed id:
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Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.
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C.E.Stebbins,
W.G.Kaelin,
N.P.Pavletich.
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ABSTRACT
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Mutation of the VHL tumor suppressor is associated with the inherited von
Hippel-Lindau (VHL) cancer syndrome and the majority of kidney cancers. VHL
binds the ElonginC-ElonginB complex and regulates levels of hypoxia-inducible
proteins. The structure of the ternary complex at 2.7 angstrom resolution shows
two interfaces, one between VHL and ElonginC and another between ElonginC and
ElonginB. Tumorigenic mutations frequently occur in a 35-residue domain of VHL
responsible for ElonginC binding. A mutational patch on a separate domain of VHL
indicates a second macromolecular binding site. The structure extends the
similarities to the SCF (Skp1-Cul1-F-box protein) complex that targets proteins
for degradation, supporting the hypothesis that VHL may function in an analogous
pathway.
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Selected figure(s)
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Figure 2.
Fig. 2. Structural elements and conservation of VHL,
ElonginC, and ElonginB. (A) Sequence of VHL demonstrating that
tumor-derived missense mutations are divided between the  and  domains of
VHL, whereas residues contacting ElonginC cluster in the domain
(40). The histogram represents 279 missense mutations in the
database (29). The six most frequently mutated amino acids are
labeled. Shaded squares above each residue describe the relative
solvent exposure of a residue in a hypothetical VHL monomer.
Blue boxes indicate residues that make hydrogen bonds or van der
Waals contacts with ElonginC. (B) Sequence identity between
human ElonginC and ElonginC homologs is indicated by yellow, and
identity between human ElonginC and human Skp1, aligned with the
program THREADER2, is indicated by green. Residues that make
hydrogen bonds or van der Waals contacts with VHL are indicated
by red and those contacting ElonginB by blue. Secondary
structure and solvent accessibility are as in (A). A disordered
segment in ElonginC is indicated with a dashed line and extended
insertions in the alignments are indicated by lines below the
sequence alignments. (C) Sequence identity between human
ElonginB and ElonginB homologs is indicated by yellow. Identity
between human ElonginB and human ubiquitin, which maps primarily
to hydrophobic core residues, is indicated by green. Residues
that make hydrogen bonds or van der Waals contacts with ElonginC
are indicated by blue. Secondary structure and solvent
accessibility are as in (A), and disordered segments in the
ElonginB structure are indicated with a dashed line. (D)
Close-up view of the - interface
of VHL. VHL amino acids are in yellow and those of ElonginC are
in cyan. White dashed lines indicate hydrogen bonds, red atoms
indicate oxygen and blue, nitrogen. A red circle with the letter
"M" indicates a residue that is one of the six most frequently
mutated in tumors.
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Figure 3.
Fig. 3. ElonginC binds VHL and ElonginB across two separate
interfaces. (A) The VHL-ElonginC interface consists of an
intermolecular hydrophobic four-helix cluster augmented by
additional contacts. VHL and ElonginC secondary structural
elements are shown in red and blue, respectively. VHL amino
acids are in yellow and those of ElonginC are in cyan. Hydrogen
bonds are indicated by white dashed lines. Red atoms indicate
oxygen and blue, nitrogen. A red circle with the letter "M"
indicates a residue that is one of the six most frequently
mutated in cancer. The ElonginC pocket where the VHL Leu^158
binds is made up of Tyr^76, Phe^93, Leu^103, and Ala^107, and
Cys^112 (40). (B) The parallel strand-
strand
interaction around which the ElonginC-ElonginB interface centers
is indicated by a two-headed arrow (four hydrogen bonds).
ElonginB and ElonginC secondary structural elements are shown in
green and blue, respectively. ElonginB amino acids are in
magenta and those of ElonginC are in cyan.
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The above figures are
reprinted
by permission from the AAAs:
Science
(1999,
284,
455-461)
copyright 1999.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.D.Sorrell,
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and
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Clinical and functional properties of novel VHL mutation (X214L) consistent with Type 2A phenotype and low risk of renal cell carcinoma.
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Clin Genet,
79,
539-545.
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A.Sarikas,
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The cullin protein family.
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PDB codes:
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N.Ito,
M.Watanabe-Matsui,
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PDB code:
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Where a reference describes a PDB structure, the PDB
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