Abstract：
:We have developed a formalism and a computational method for analyzing the potential functional consequences of non-synonymous single nucleotide polymorphisms. Our approach uses a structural model and phylogenetic information to derive a selection of structure and sequence-based features serving as indicators of an amino acid polymorphim's effect on function. The feature values can be integrated into a probabilistic assessment of whether an amino acid polymorphism will affect the function or stability of a target protein. The method has been validated with data sets of unbiased mutations in the lac repressor and lysoyzyme. Applying our methodology to recent surveys of genetic variation in the coding regions of clinically important genes, we estimate that approximately 26-32 % of the natural non-synonymous single nucleotide polymorphisms have effects on function. This estimate suggests that a typical person will have about 6240-12,800 heterozygous loci that encode proteins with functional variation due to natural amino acid polymorphism.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Chasman D,Adams RMdoi
10.1006/jmbi.2001.4510keywords:
subject
Has Abstractpub_date
2001-03-23 00:00:00pages
683-706issue
2eissn
0022-2836issn
1089-8638pii
S0022-2836(01)94510-3journal_volume
307pub_type
杂志文章abstract：:The evolution of new or improved enzyme specificities in prokaryotes has been proposed to involve gene duplication, followed by silencing of one of the duplicates at the transcriptional or translational level. Such "silent gene intermediates" are distinct from "cryptic" genes, which are proposed to have a different ro...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(86)90358-x
更新日期：1986-11-20 00:00:00
abstract：:Although LEDGF/p75 is believed to act as a cellular cofactor of lentiviral integration by tethering integrase (IN) to chromatin, there is no good in vitro model to analyze this functionality. We designed an AlphaScreen assay to study how LEDGF/p75 modulates the interaction of human immunodeficiency virus type 1 IN wit...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2011.03.073
更新日期：2011-07-29 00:00:00
abstract：:Drugs can affect function in proteins by modulating their flexibility. Despite this possibility, there are very few studies on how drug binding affects the dynamics of target macromolecules. FKBP12 (FK506 binding protein 12) is a prolyl cis-trans isomerase and a drug target. The immunosuppressant drug rapamycin exerts...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2010.10.037
更新日期：2011-01-14 00:00:00
abstract：:An in vitro assay in which terminating Escherichia coli ribosomes with different stop signals in the A-site compete for a limited amount of a release factor (RF1 or RF2) has been used to estimate the relative termination efficiencies at stop codons with different adjacent downstream nucleotides. The assay allows direc...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1998.2220
更新日期：1998-12-04 00:00:00
abstract：:The excessive activity of matrix metalloproteinases (MMPs) contributes to pathological processes such as arthritis, tumor growth and metastasis if not balanced by the tissue inhibitors of metalloproteinases (TIMPs). In arthritis, the destruction of fibrillar (type II) collagen is one of the hallmarks, with MMP-1 (coll...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2006.11.072
更新日期：2007-03-02 00:00:00
abstract：:Interactions of rat DNA polymerase beta with a single-stranded (ss) DNA have been studied using the quantitative fluorescence titration technique. Examination of the fluorescence changes accompanying the binding, as a function of the thermodynamically rigorous binding density of rat pol beta-ssDNA complexes, reveals t...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1998.2252
更新日期：1998-12-11 00:00:00
abstract：:Four subunits of the F1F0-ATPase from bovine heart mitochondria have been produced by heterologous over-expression in Escherichia coli. They are the oligomycin sensitivity conferral protein (OSCP), coupling factor 6 (F6) and subunits b and d. Likewise, fragments b', bI, bC, and bM (amino acid residues 79 to 214, 121 t...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1994.1591
更新日期：1994-09-30 00:00:00
abstract：:Mutational experiments show how changes in the hydrophobic cores of proteins affect their stabilities. Here, we estimate these effects computationally, using four-body likelihood potentials obtained by simplicial neighborhood analysis of protein packing (SNAPP). In this procedure, the volume of a known protein structu...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.2001.4906
更新日期：2001-08-24 00:00:00
abstract：:In order to develop a system which allows infection by an epitope-specific phage-antibody via an F-pilus expressing that epitope, a study on the expression of foreign sequences on F-pilin was undertaken. Initially, a plasmid library was constructed with random sequences encoding one to five amino acid residues fused t...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1998.1773
更新日期：1998-06-12 00:00:00
abstract：:It has been well established that a single amino acid sequence can give rise to several conformationally distinct amyloid states. The extent to which amyloid structures formed within the same sequence are different, however, remains unclear. To address this question, we studied two amyloid states (referred to as R- an...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2010.05.051
更新日期：2010-07-23 00:00:00
abstract：:The two-domain, 325 residue outer membrane protein OmpA is one of the most abundant proteins of Escherichia coli, playing a role in the maintenance of the integrity of the cell surface. The N-terminal domain, consisting of about 170 amino acid residues, is embedded in the membrane, presumably in the form of a beta-bar...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1995.0403
更新日期：1995-07-28 00:00:00
abstract：:6A6 is a murine monoclonal antibody raised against the humanized anti-tissue factor antibody D3H44. 6A6 is able to completely neutralize the anticoagulant activity of D3H44 in tissue factor-dependent functional assays, such as endotoxin-induced whole blood clotting, prothrombin time, as well as factor X and factor IX ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/s0022-2836(03)00735-6
更新日期：2003-08-08 00:00:00
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journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1996.0855
更新日期：1997-03-28 00:00:00
abstract：:Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2010.05.024
更新日期：2010-07-16 00:00:00
abstract：:The 8-17 deoxyribozyme is an in vitro selected enzyme capable of sequence-specific cleavage of RNA. While selected to be a magnesium and zinc-utilizing enzyme, the 8-17 DNAzyme has been shown to utilize lead for its catalysis. Fluorescence-based experiments have indicated that the magnesium- and zinc-utilizing version...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2009.11.028
更新日期：2010-01-15 00:00:00
abstract：:The three-dimensional structure of the bacteriophage T7 head-to-tail connector has been obtained at 8A resolution using cryo-electron microscopy and single-particle analysis from purified recombinant connectors. The general morphology of the T7 connector is that of a 12-folded toroidal homopolymer with a channel that ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2005.02.005
更新日期：2005-04-15 00:00:00
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journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2005.02.070
更新日期：2005-05-20 00:00:00
abstract：:Two site-directed mutants of Escherichia coli DNA helicase II (UvrD) were constructed to examine the functional significance of motif VI in a superfamily I helicase. Threonine 604 and arginine 605, representing two of the most highly conserved residues in motif VI, were replaced with alanine, generating the mutant all...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1997.1614
更新日期：1998-03-27 00:00:00
abstract：:A new statistic Sc, which has a number of advantages over other measures of packing, is used to examine the shape complementarity of protein/protein interfaces selected from the Brookhaven Protein Data Bank. It is shown using Sc that antibody/antigen interfaces as a whole exhibit poorer shape complementarity than is o...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1993.1648
更新日期：1993-12-20 00:00:00
abstract：:Antisense RNAs interact with their complementary target RNAs as folded structures. The formation of early binding intermediates is the most important step in determining the overall rates of stable complex formation in vitro and the efficiency of control in vivo. In the case of CopA and CopT (antisense/target RNA pair...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.2001.4802
更新日期：2001-07-27 00:00:00
abstract：:A protein microarray system containing different dilutions of 77 related and non-related proteins was used to show that IgE from subjects allergic to Brazil nut specifically recognise the seed 2S albumin protein (Ber e 1). Further, correctly folded chimaeric 2S albumin proteins containing structural epitope replacemen...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2004.08.065
更新日期：2004-10-22 00:00:00
abstract：:The DNA sequences of the entire coding regions of the A and C type variable surface protein genes from Paramecium tetraurelia, stock 51 have been determined. The 8151 nucleotide open reading frame of the A gene contains several tandem repeats of 210 nucleotides within the central portion of the molecule as well as a p...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/0022-2836(91)90573-o
更新日期：1991-12-20 00:00:00
abstract：:Hepatitis B virus is a major human pathogen that consists of a viral genome surrounded by an icosahedrally ordered core protein and a polymorphic, lipidic envelope that is densely packed with surface proteins. A point mutation in the core protein in which a phenylalanine at position 97 is exchanged for a smaller leuci...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2018.10.018
更新日期：2018-12-07 00:00:00
abstract：:A homologue of the Escherichia coli GroEL apical domain was obtained from thermophilic eubacterium Thermus thermophilus. The domains share 70 % sequence identity (101 out of 145 residues). The thermal stability of the T. thermophilus apical domain (Tm>100 degrees C as evaluated by circular dichroism) is at least 35 de...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.2000.4405
更新日期：2001-02-23 00:00:00
abstract：:The 37/ 67-kDa human laminin receptor (LamR) is a cell surface receptor for laminin, prion protein, and a variety of viruses. Because of its wide range of ligands, LamR plays a role in numerous pathologies. LamR overexpression correlates with a highly invasive cell phenotype and increased metastatic ability, mediated ...
journal_title：Journal of molecular biology
pub_type： 杂志文章,评审
doi：10.1016/j.jmb.2010.10.028
更新日期：2011-01-07 00:00:00
abstract：:Folding kinetics of large RNAs are just beginning to be investigated. We show that the Tetrahymena self-splicing RNA partitions into a population that rapidly reaches the native state, and a slowly folding population that is trapped in metastable misfolded structures. Transitions from the misfolded structures to the n...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1997.1311
更新日期：1997-10-17 00:00:00
abstract：:The crystal structure of abrin-a, a type II ribosome-inactivating protein from the seeds of Abrus precatorius, has been determined from a novel crystalline form by the molecular replacement method using the coordinates of ricin. The structure has been refined at 2.14 A to a R-factor of 18.9%. The root-mean-square devi...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1995.0382
更新日期：1995-07-14 00:00:00
abstract：:The bacteriophage T4 replication origins ori(uvsY) and ori(34) each contain two distinct components: a T4 middle-mode promoter that is strictly required for replication and a downstream region of about 50 bp that is required for maximal levels of replication. Here, we present evidence that structure of the downstream ...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1006/jmbi.1996.0844
更新日期：1997-03-14 00:00:00
abstract：:The viral RNA-dependent RNA polymerases show a conserved structure where the fingers domain interacts with the top of the thumb domain to create a tunnel through which nucleotide triphosphates reach the active site. We have solved the crystal structures of poliovirus polymerase (3D(pol)) in complex with all four NTPs,...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/j.jmb.2006.11.070
更新日期：2007-03-09 00:00:00
abstract：:The observed propeller twist in base-pairs of crystalline double-helical DNA oligomers improves the stacking overlap along each individual helix strand. But, as proposed by Calladine, it also leads to clash or steric hindrance between purines at adjacent base-pairs on opposite strands of the helix. This clash can be r...
journal_title：Journal of molecular biology
pub_type： 杂志文章
doi：10.1016/s0022-2836(83)80093-x
更新日期：1983-05-25 00:00:00
