Abstract:
:The central structural feature of natural proteins is a tightly packed and highly ordered hydrophobic core. If some measure of exquisite, native-like core packing is necessary for enzymatic function, this would constitute a significant obstacle to the development of novel enzymes, either by design or by natural or experimental evolution. To test the minimum requirements for a core to provide sufficient structural integrity for enzymatic activity, we have produced mutants of the ribonuclease barnase in which 12 of the 13 core residues have together been randomly replaced by hydrophobic alternatives. Using a sensitive biological screen, we find that a strikingly high proportion of these mutants (23%) retain enzymatic activity in vivo. Further substitution at the 13th core position shows that a similar proportion of completely random hydrophobic cores supports enzyme function. Of the active mutants produced, several have no wild-type core residues. These results imply that hydrophobicity is nearly a sufficient criterion for the construction of a functional core and, in conjunction with previous studies, that refinement of a crudely functional core entails more stringent sequence constraints than does the initial attainment of crude core function. Since attainment of crude function is the critical initial step in evolutionary innovation, the relatively scant requirements contributed by the hydrophobic core would greatly reduce the initial hurdle on the evolutionary pathway to novel enzymes. Similarly, experimental development of novel functional proteins might be simplified by limiting core design to mere specification of hydrophobicity and using iterative mutation-selection to optimize core structure.
journal_name
Proc Natl Acad Sci U S Aauthors
Axe DD,Foster NW,Fersht ARdoi
10.1073/pnas.93.11.5590subject
Has Abstractpub_date
1996-05-28 00:00:00pages
5590-4issue
11eissn
0027-8424issn
1091-6490journal_volume
93pub_type
杂志文章abstract::Conclusive proof that the mouse egg is capable of carrying out repair of genetic lesions present in the male genome was obtained through dominant-lethal studies of chemically treated spermatozoa and spermatids and through cytological analysis of first-cleavage metaphases. The maximum difference in repair capability be...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.1.435
更新日期:1979-01-01 00:00:00
abstract::A light beam hitting the retina produces an excitatory process; however, around the edge of the light beam, sensory cells are inhibited and lose their sensitivity. This combination of stimulation and inhibition produces a discrepancy between the luminance pattern presented to the eye and the brightness pattern that is...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.69.4.885
更新日期:1972-04-01 00:00:00
abstract::Conflict between groups of individuals is a prevalent feature in human societies. A common theoretical explanation for intergroup conflict is that it provides benefits to individuals within groups in the form of reproduction-enhancing resources, such as food, territory, or mates. However, it is not always the case tha...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1810404116
更新日期:2019-07-09 00:00:00
abstract::Single molecule atomic force microscopy was used to characterize structure, binding strength (unbinding force), and binding kinetics of a classical cadherin, vascular endothelial (VE)-cadherin, secreted by transfected Chinese hamster ovary cells as cis-dimerized full-length external domain fused to Fc-portion of human...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.070052697
更新日期:2000-04-11 00:00:00
abstract::Platelet-derived growth factor receptor (PDGFR) signaling is essential for normal embryonic development in many organisms, including frog, mouse, zebrafish, and sea urchin. The mode of action of PDGFR signaling during early development is poorly understood, however, mostly because inhibition of signaling through eithe...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0502885102
更新日期:2005-06-07 00:00:00
abstract::The amino acid sequence of blastokinin, also called uteroglobin, has been determined by a combined study of both the intact native molecule and the peptide fragments resulting from tryptic and chymotryptic digestions. Sequence analyses performed by automated methods and by sequential digestion with leucine aminopeptid...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.75.11.5516
更新日期:1978-11-01 00:00:00
abstract::Beyond state-of-the-art lithium-ion battery (LIB) technology with metallic lithium anodes to replace conventional ion intercalation anode materials is highly desirable because of lithium's highest specific capacity (3,860 mA/g) and lowest negative electrochemical potential (∼3.040 V vs. the standard hydrogen electrode...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1600422113
更新日期:2016-06-28 00:00:00
abstract::Glial fibrillary acidic protein (GFAP) is a member of the family of intermediate filament structural proteins and is found predominantly in astrocytes of the central nervous system (CNS). To assess the function of GFAP, we created GFAP-null mice using gene targeting in embryonic stem cells. The GFAP-null mice have nor...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.93.13.6361
更新日期:1996-06-25 00:00:00
abstract::It has recently been demonstrated that coupled enzymatic processes may possess, for a particular choice of the state variables, multidimensional inflection points in thermodynamic force-flow space. The conditions for reciprocity in the linear region near such a reference state, which may be far from equilibrium, are o...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.78.7.4314
更新日期:1981-07-01 00:00:00
abstract::Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis. The underlying mechanisms are poorly understood, and investigations have been hampered by the absence of animal models that reflect the human condition of generalized atherosclerosis and lupus. We addressed this problem by transferring ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0602311103
更新日期:2006-05-02 00:00:00
abstract::The two internal transcribed spacers (ITS1 and ITS2) of rDNA of three members of the Ixodes ricinus "complex" (Acari: Ixodidae) were sequenced. Sequence variation was assessed for the North American species I. scapularis, I. dammini, and I. pacificus at three levels: within individual/population, between individuals o...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.90.21.10221
更新日期:1993-11-01 00:00:00
abstract::The role of cell surface immunoglobulin in helper T-cell-dependent B-cell activation was analyzed using a B-cell lymphoma, CH12, with known antigen specificity and activation properties similar to those of a resting B cell. Two sources of helper T cells were used, both selected such that they interact with H-2-encoded...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.8.2466
更新日期:1984-04-01 00:00:00
abstract::A major barrier to the design of immunotherapeutics and vaccines for cancer is the idiosyncratic nature of many tumor antigens and the possibility that T cells may be tolerant of broadly distributed antigens. We have devised an experimental strategy that exploits species differences in protein sequences to circumvent ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.92.26.11993
更新日期:1995-12-19 00:00:00
abstract::In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although (2)H(2)O labeling in young mice showed high thymic-dependent daily naïve T cell production, long te...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.0709713105
更新日期:2008-04-22 00:00:00
abstract::In HL-60 cells, a human promyelocytic leukemia cell line, the human c-myc gene, designated MYC, is amplified about 16-fold. On differentiation of the HL-60 cells into granulocytes induced by several inhibitors of poly(ADP-ribose) polymerase [NAD+ poly(adenosine diphosphate D-ribose)ADP-D-ribosyltransferase, EC 2.4.2.3...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.86.19.7442
更新日期:1989-10-01 00:00:00
abstract::The effects of temperature and of the action of a purified phospholipase C enzyme preparation on human red blood cell membranes has been investigated by chemical analyses, circular dichroism, and proton magnetic resonance measurements. The results indicate that a substantial fraction of the phospholipids and the prote...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.65.3.721
更新日期:1970-03-01 00:00:00
abstract::Plasma growth hormone (GH) profiles are sexually differentiated in many species and regulate the sex-dependence of peripubescent growth rates and liver function, including steroid hydroxylase cytochrome P450 expression, by mechanisms that are poorly understood. By use of an external pump to deliver to hypophysectomize...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.88.15.6868
更新日期:1991-08-01 00:00:00
abstract::Volume changes associated with protein folding reactions contain valuable information about the folding mechanism and the nature of the transition state. However, meaningful interpretation of such data requires that overall volume changes be deconvoluted into individual contributions from different structural componen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1317973110
更新日期:2013-12-24 00:00:00
abstract::Monovalent antibodies (Fab) directed to two classes of transformation-sensitive cell surface components, ganglioside and galactoprotein a (Gap a), inhibit the process of oncogenic viral transformation of cells. Mouse 3T3 cells infected with murine sarcoma virus were not transformed in terms of morphology change and en...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.75.12.6049
更新日期:1978-12-01 00:00:00
abstract::Poly([14C]adenosine diphosphate ribose) was synthesized from [14C]NAD+ with calf thymus nuclei. The fraction containing poly(adenosine diphosphate ribose) eluted with 0.22--0.40 M phosphate buffer (pH 6.8) from a hydroxylapatite column, was completely hydrolyzed with venom phosphodiesterase, and was separated by DEAE-...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.76.2.595
更新日期:1979-02-01 00:00:00
abstract::An unstable allele of the bronze 2 (bz2) locus was isolated from a Robertson's Mutator Zea mays line containing a family of active transposable Mu elements. This mutation is somatically unstable, resulting in numerous revertant purple sectors on a bronze kernel. By following the variegated kernel phenotype through two...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.83.6.1767
更新日期:1986-03-01 00:00:00
abstract::A mutation that confers resistance to the drug paromomycin is shown to be in the structural gene that codes for the ribosomal RNA in Tetrahymena. This observation was made by exploiting a variant of the ribosomal DNA that distorts amplification of this locus when a new somatic nucleus develops during conjugation. Beca...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.9.2844
更新日期:1985-05-01 00:00:00
abstract::The primary structure and phosphorylation pattern of the tandem Y(1)S(2)P(3)T(4)S(5)P(6)S(7) repeats of the RNA polymerase II carboxyl-terminal domain (CTD) convey information about the transcription apparatus--a CTD code--to a large ensemble of CTD-binding receptor proteins. Four of the seven coding "letters" of the ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1208995109
更新日期:2012-10-30 00:00:00
abstract::Characteristic classes for the index of the Dirac family [unk](A) are computed in terms of differential forms on the orbit space of vector potentials under gauge transformations. They represent obstructions to the existence of a covariant Dirac propagator. The first obstruction is related to a chiral anomaly. ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.81.8.2597
更新日期:1984-04-01 00:00:00
abstract::We previously have shown that proliferating lymphoid cells contain an extractable cytoplasmic protein that is capable of inducing DNA synthesis in isolated quiescent nuclei (activator of DNA replication, ADR). ADR is present in continuously proliferating (transformed) lymphoblastoid cell lines and in mitogen- or inter...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.82.15.5160
更新日期:1985-08-01 00:00:00
abstract::The solar system formed from interstellar dust and gas in a molecular cloud. Astronomical observations show that typical interstellar dust consists of amorphous (a-) silicate and organic carbon. Bona fide physical samples for laboratory studies would yield unprecedented insight about solar system formation, but they w...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1720167115
更新日期:2018-06-26 00:00:00
abstract::The mammalian innate immune system uses several sensors of double-stranded RNA (dsRNA) to develop the interferon response. Among these sensors are dsRNA-activated oligoadenylate synthetases (OAS), which produce signaling 2',5'-linked RNA molecules (2-5A) that activate regulated RNA decay in mammalian tissues. Differen...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1419409112
更新日期:2015-03-31 00:00:00
abstract::The fundamental questions of how lubricant molecules organize into a layered structure under nanometers confinement and what is the interplay between layering and friction are still not well answered in the field of nanotribology. While the phase transition of lubricants during a squeeze-out process under compression ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1805569115
更新日期:2018-06-26 00:00:00
abstract::Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, ...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1321207111
更新日期:2014-06-10 00:00:00
abstract::Little is known about how genetic variation and epigenetic marks interact to shape differences in behavior. The foraging (for) gene regulates behavioral differences between the rover and sitter Drosophila melanogaster strains, but the molecular mechanisms through which it does so have remained elusive. We show that th...
journal_title:Proceedings of the National Academy of Sciences of the United States of America
pub_type: 杂志文章
doi:10.1073/pnas.1710770114
更新日期:2017-11-21 00:00:00