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Literature summary for 1.14.14.16 extracted from

  • Haider, S.; Islam, B.; DAtri, V.; Sgobba, M.; Poojari, C.; Sun, L.; Yuen, T.; Zaidi, M.; New, M.I.
    Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia (2013), Proc. Natl. Acad. Sci. USA, 110, 2605-2610.
    View publication on PubMedView publication on EuropePMC

Protein Variants

Protein Variants Comment Organism
A265C naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
A265V naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
A391T naturally occuring mutation, the mutation disrupts the hydrophobicity of the region Homo sapiens
A434V naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive Homo sapiens
C169R naturally occuring mutation, the mutation alters the region's hydrophobicity, conserved residue C169 makes hydrophobic interactions with the loop between E-F helices and F-helix Homo sapiens
D322G naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
D407N naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
E320K naturally occuring mutation, the mutation of E320, which is a highly conserved residue on a negatively charged Glu-Glu-Leu-Asp (EELD) motif, alters the charge on the motif Homo sapiens
E431K naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
F404S naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia Homo sapiens
G178A naturally occuring mutation, the mutation causes reduced structural flexibility of the sharp fold between the E- and F-helices Homo sapiens
G291C naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia Homo sapiens
G291R naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia Homo sapiens
G291S naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia Homo sapiens
G292D naturally occuring mutation, the mutation abolishes substrate binding causing salt-wasting congenital adrenal hyperplasia Homo sapiens
G424S naturally occuring mutation, the mutation imparts rigidity to the loop between K'- and L-helix Homo sapiens
G56R naturally occuring mutation, P57 and G56 form the hinge between the membrane interacting N-terminus and rest of the protein. The substitution of G56 with a polar and rigid Arg residue disrupts the hinge affecting the interactions of CYP21A2 with the membrane Homo sapiens
G90V naturally occuring mutation, mutation of G90 to valine affects the ability of R91 to hydrogen bond with heme, causing salt-wasting congenital adrenal hyperplasia Homo sapiens
H119R naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
H365Y naturally occuring mutation, the mutations causes the salt-wasting disease Homo sapiens
H62L naturally occuring mutation, the mutation may disrupt hydrogen bonding to reduce, but not eliminate, enzyme activity Homo sapiens
I172N naturally occuring mutation, the mutation causes a loss of the hydrophobic pocket, I172 forms a hydrophobic pocket with M186 and M187 residues of F-helix Homo sapiens
I194N naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
I230T naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
I77T naturally occuring mutation, the mutation disrupts the hydrophobic environment Homo sapiens
K121Q naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
L107R naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia Homo sapiens
L142P naturally occuring mutation, the mutation of the D-helix causes helical disruption and destabilization of secondary structures Homo sapiens
L166P naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures Homo sapiens
L167P naturally occuring mutation, the mutation of the E-helix causes helical disruption and destabilization of secondary structures Homo sapiens
L261P naturally occuring mutation, the mutation of the H-helix causes helical disruption and destabilization of secondary structures Homo sapiens
L300F naturally occuring mutation, the mutation causes localized destabilization of secondary structure Homo sapiens
L307M naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment Homo sapiens
L307V naturally occuring mutation, the mutation disrupts the optimal packing of side chains but does not alter the hydrophobic environment Homo sapiens
L308F naturally occuring mutation, the mutation causes localized destabilization of secondary structure Homo sapiens
L353R naturally occuring mutation, the mutation abolishes heme binding and causes salt-wasting congenital adrenal hyperplasia Homo sapiens
L363W naturally occuring mutation, the mutation causes steric clashes with the heme rendering the enzyme almost inactive Homo sapiens
L446P naturally occuring mutation, the mutation of the L-helix causes helical disruption and destabilization of secondary structures Homo sapiens
N387K naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
P30E naturally occuring mutation causing disruption of the interaction between the carbon of P30 in the N-terminal loop and the side chain of Y376 within the beta5-beta6 hairpin loop resuting in the salt-wasting disease Homo sapiens
P432L naturally occuring mutation, the mutation makes the structure more flexible and prevents cysteine from being presented to heme Homo sapiens
P453S naturally occuring mutation, the mutation disrupts the hydrophobicity of the region Homo sapiens
P459H naturally occuring mutation, the mutation disrupts the hydrophobicity of the region Homo sapiens
P463L naturally occuring mutation, the mutation interferes with the conformation of the beta8-beta9 loop with the subsequent closure of substrate entrance channel Homo sapiens
Q481P naturally occuring mutation, the mutation destabilizes the structure rendering the protein inactive Homo sapiens
R124H naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
R132C naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
R149C naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
R233G naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype Homo sapiens
R233K naturally occuring mutation, the mutation may prevent R233 from binding to the 3-keto oxygen of the proximal 17OHP in the proper orientation, it does not influence protein activity significantly, resulting in minimal phenotype Homo sapiens
R339H naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
R341P naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
R341W naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
R356P naturally occuring mutation, the mutation disrupts the interaction of R356 with Q389 rendering the enzyme inactive and causing salt-wasting congenital adrenal hyperplasia Homo sapiens
R369Q naturally occuring mutation, the mutation impairs the interaction with the P450 oxidoreductase Homo sapiens
R408C/L naturally occuring mutation, the mutation destabilizes structural elements because of the extensive loss of hydrogen bonds Homo sapiens
R408H naturally occuring mutation, the mutation prevents normal hydrogen bonding with E351 and R354 Homo sapiens
R426C naturally occuring mutation, the mutation disrupts the interaction of residues R91 and R426 rendering the protein nonfunctional and causing salt-wasting congenital adrenal hyperplasia Homo sapiens
R435C naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
R479L naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
R483P naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
R483Q naturally occuring mutation, the mutation prevents salt bridge formation resulting in a localized, as opposed to global, destabilization of tertiary structure Homo sapiens
S301Y naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
T168N naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
T295X naturally occuring mutation, the mutation abolishes substrate binding and causes salt-wasting congenital adrenal hyperplasia Homo sapiens
T450P naturally occuring mutation, the mutation reduces flexibility of beta8-sheet, which helps stabilize the very long C-terminal loop Homo sapiens
V139E naturally occuring mutation, mutation to glutamate disrupts the interaction with residues V440 and L436 on the L-helix causing instability of the enzyme, charge repulsions between the side chain of mutated V139E and E437 of the E-helix render the protein unstable and inactive causing salt-wasting congenital adrenal hyperplasia Homo sapiens
V249A naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
V281G naturally occuring mutation, the mutation causes a loss of the hydrophobic pocket Homo sapiens
V304M naturally occuring mutation, the mutation causes side-chain steric clashes with the neighboring residues Homo sapiens
W302R naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia Homo sapiens
W302S naturally occuring mutation, the mutation prevents stable packing interactions resulting in salt-wasting congenital adrenal hyperplasia Homo sapiens
Y47C naturally occuring mutation, the mutation disables hydrogen bonding with H38, the interaction is compensated by a weak His-Cys interaction Homo sapiens
Y47L naturally occuring mutation, the mutation disrupts hydrogen bonds and causes salt-wasting congenital adrenal hyperplasia Homo sapiens
Y59N naturally occuring mutation, the mutation disrupts the hydrophobicity of the region resulting in loss of function Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
endoplasmic reticulum membrane bound Homo sapiens 5789
-

Metals/Ions

Metals/Ions Comment Organism Structure
Fe2+ heme enzyme Homo sapiens

Organism

Organism UniProt Comment Textmining
Homo sapiens P08686 gene CYP21A2
-

Source Tissue

Source Tissue Comment Organism Textmining

Synonyms

Synonyms Comment Organism
CYP21A2
-
Homo sapiens
cytochrome p450 21A2
-
Homo sapiens
Steroid 21-hydroxylase
-
Homo sapiens

Cofactor

Cofactor Comment Organism Structure
heme
-
Homo sapiens

General Information

General Information Comment Organism
malfunction mutations in the cytochrome p450 (CYP)21A2 gene, which encodes the enzyme steroid 21-hydroxylase, cause the majority of cases in congenital adrenal hyperplasia, an autosomal recessive disorder. The mutations can be associated either with severe salt-wasting or simple virilizing phenotypes or with milder nonclassical phenotypes, structure-phenotype correlations, overview. Mutations that affect membrane anchoring, disrupt heme and/or substrate binding, or impair stability of CYP21A2 cause complete loss of function and salt-wasting disease, while mutations altering the transmembrane region or conserved hydrophobic patches cause up to a 98% reduction in enzyme activity and simple virilizing disease Homo sapiens
additional information structure homology modelling using bovine CYP21A2 crystal structure as template. Close contact between the carbon of P30 in the N-terminal loop and the side chain of Y376 within the beta5-beta6 hairpin loop is critical for protein folding Homo sapiens