New applications of simulated annealing in X-ray crystallography and solution NMR

Brünger, A.T.; Adams, Paul D.; Rice, Luke M.

doi:10.1016/s0969-2126(97)00190-1

Cited by 346 publications

(346 citation statements)

References 78 publications

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“…Electron density maps calculated using combined phases from SHARP and the partial model resulted in a marked improvement in map quality and allowed for rapid building of the model. Composite omit maps (20) were used to ensure proper registration and to rule out mistracing of the backbone. When 160 of 164 residues were built (R work ) 25.2% and R free ) 29.7%), the model was used to provide initial phases for the isomorphous high-resolution (1.9 Å) native data set.…”

Section: Methodsmentioning

confidence: 99%

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,

et al. 2004

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The haloacid dehalogenase (HAD) superfamily is comprised of structurally homologous enzymes that share several conserved sequence motifs (loops I-IV) in their active site. The majority of HAD members are phosphohydrolases and may be divided into three subclasses depending on domain organization. In classes I and II, a mobile "cap" domain reorients upon substrate binding, closing the active site to bulk solvent. Members of the third class lack this additional domain. Herein, we report the 1.9 Å X-ray crystal structures of a member of the third subclass, magnesium-dependent phosphatase-1 (MDP-1) both in its unliganded form and with the product analogue, tungstate, bound to the active site. The secondary structure of MDP-1 is similar to that of the "core" domain of other type I and type II HAD members with the addition of a small, 28-amino acid insert that does not close down to exclude bulk solvent in the presence of ligand. In addition, the monomeric oligomeric state of MDP-1 does not allow the participation of a second subunit in the formation and solvent protection of the active site. The binding sites for the phosphate portion of the substrate and Mg(II) cofactor are also similar to those of other HAD members, with all previously observed contacts conserved. Unlike other subclass III HAD members, MDP-1 appears to be equally able to dephosphorylate phosphotyrosine and closed-ring phosphosugars. Modeling of possible substrates in the active site of MDP-1 reveals very few potential interactions with the substrate leaving group. The mapping of conserved residues in sequences of MDP-1 from different eukaryotic organisms reveals that they colocalize to a large region on the surface of the protein outside the active site. This observation combined with the modeling studies suggests that the target of MDP-1 is most likely a phosphotyrosine in an unknown protein rather than a small sugar-based substrate.

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Section: Methodsmentioning

confidence: 99%

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,

et al. 2004

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“…31 NMR-restrained molecular dynamics computations were performed essentially as described previously. 20a Folding of the five-residue A16-G17-G18-A19-G20 loop was facilitated by hydrogen bond restraints on the Watson-Crick A16•G20 base pair.…”

Section: Structure Calculationmentioning

confidence: 99%

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

et al. 2007

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The c-kit oncogene is an important target in the treatment of gastrointestinal tumors. A potential approach to inhibition of the expression of this gene involves selective stabilization of Gquadruplex structures that may be induced to form in the c-kit promoter region. Here we report on the structure of an unprecedented intramolecular G-quadruplex formed by a G-rich sequence in the c-kit promoter in K + solution. The structure represents a new folding topology with several unique features. Most strikingly, an isolated guanine is involved in G-tetrad core formation, despite the presence of four three-guanine tracts. There are four loops: two single-residue double-chainreversal loops, a two-residue loop, and a five-residue stem-loop, which contain base-pairing alignments. This unique structural scaffold provides a highly specific platform for the future design of ligands specifically targeted to the promoter DNA of c-kit.

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“…Final structures were calculated using simulated annealing and energy minimization protocols within CNS version 1.1 (22). The starting structures were generated using random ( , ) dihedral angles and energy-minimized to produce structures with the correct local geometry.…”

Section: Materials-t-butoxycarbonylmentioning

confidence: 99%

Conopressin-T from Conus tulipa Reveals an Antagonist Switch in Vasopressin-like Peptides

Dutertre

Croker²,

Daly

et al. 2008

Journal of Biological Chemistry

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We report the discovery of conopressin-T, a novel bioactive peptide isolated from Conus tulipa venom. Conopressin-T belongs to the vasopressin-like peptide family and displays high sequence homology to the mammalian hormone oxytocin (OT) and to vasotocin, the endogenous vasopressin analogue found in teleost fish, the cone snail's prey. Conopressin-T was found to act as a selective antagonist at the human V 1a receptor. All peptides in this family contain two conserved amino acids within the exocyclic tripeptide (Pro 7 and Gly 9 ), which are replaced with Leu 7 and Val 9 in conopressin-T. Whereas conopressin-T binds only to OT and V 1a receptors, an L7P analogue had increased affinity for the V 1a receptor and weak V 2 receptor binding. Surprisingly, replacing Gly 9 with Val 9 in OT and vasopressin revealed that this position can function as an agonist/antagonist switch at the V 1a receptor. NMR structures of both conopressin-T and L7P analogue revealed a marked difference in the orientation of the exocyclic tripeptide that may serve as templates for the design of novel ligands with enhanced affinity for the V 1a receptor.The vasopressin (AVP) 3 and oxytocin (OT) peptides were originally discovered and identified as neurohypophysial hormones in mammals (1). In humans, AVP acts via three vasopressin receptors (vascular V 1a R, pituitary V 1b R, and renal V 2 R), whereas OT acts via one OT receptor (OTR). All targets are members of the G protein-coupled receptor family (2). Peripherally, they regulate water balance, the control of blood pressure, and contraction of uterine smooth muscle and mammary myoepithelium (3). Centrally, these peptides affect levels of aggression, depression, and young parent bonding (4 -6). Endogenous analogues of OT and AVP have been reported in nonmammalian vertebrates, annelids, molluscs, and insects, suggesting an old lineage for these peptides (7). Surprisingly, two variants were also found in the venom of predatory cone snails. The original discovery of these two AVP analogues, named conopressins, was based on the characteristic "scratching" effect observed upon intracerebral injection into mice (8). Although the sequences of conopressins are similar to vasopressin itself, they have an additional positive charge in position 4, which is only found in two other endogenous vasopressin analogues, cephalotocin (Octopus vulgaris) and annetocin (Eisenia foetida). Conopressin-S was isolated from Conus striatus, whereas conopressin-G was first isolated from Conus geographus venom but later found in Conus imperialis venom as well as in tissue extracts of the nonvenomous snails Lymnea stagnalis and Aplysia californica and the leech Erpobdella octoculata (9 -11).Molluscs of the genus Conus produce bioactive peptides in a combinatorial fashion. As demonstrated for the snake toxins (12), most conotoxins or conopeptides are believed to be derived from an endogenous structural template (13). Because conopressin-G is widely distributed, it may represent the endogenous hormone in Gastropods and Annelid...

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New applications of simulated annealing in X-ray crystallography and solution NMR

Cited by 346 publications

References 78 publications

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

Conopressin-T from Conus tulipa Reveals an Antagonist Switch in Vasopressin-like Peptides

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New applications of simulated annealing in X-ray crystallography and solution NMR

Cited by 346 publications

References 78 publications

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily,

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily,

Structure of an Unprecedented G-Quadruplex Scaffold in the Human c-kit Promoter

Conopressin-T from Conus tulipa Reveals an Antagonist Switch in Vasopressin-like Peptides

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Product

Resources

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X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,

X-ray Crystal Structure of the Hypothetical Phosphotyrosine Phosphatase MDP-1 of the Haloacid Dehalogenase Superfamily^,