Stereochemical criteria for polypeptides and proteins. IV. Standard dimensions for the <i>cis</i>‐peptide unit and conformation of cis‐polypeptides

Ramachandran, G.; Venkatachalam, C. M.

doi:10.1002/bip.1968.360060903

Cited by 53 publications

(17 citation statements)

References 6 publications

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“…Recent crystallographic data (21) and measurements of the characteristic ratio of poly(iproline) (22) indicate that this is a reasonable structure for proline. There is evidence that peptide bonds involving proline can undergo trans -a cis isomerization (23,24), and when such isomerization occurs there is likely to be a change in bond angles around the peptide N atom (19,20). Our calculations are performed with fixed geometry.…”

Section: Geometry Of Trfmentioning

confidence: 99%

Conformational Analysis of Thyrotropin Releasing Factor

Burgess

Momany

Scheraga

1973

Proc. Natl. Acad. Sci. U.S.A.

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authors have requested readers to note that a p-D-glutamyl residue rather than the p-LIglutamyl residue, implied in the text, was used for the calculations. The conclusions drawn in the paper are correct, since the D and L configurations of the p-glutamyl residue adopt almost identical conformations in thyrotropin releasing factor (TRF). It is possible to use the results in Tables 2-4 of the original paper to obtain the lowenergy conformations of TRF by simply reversing the sign of {,. The conformations thus obtained will not be the exact energy minima, but will represent all of the low-energy conformations closely. In order to illustrate this point, the calculations of Table 2 in the original text (for "p-D-glutamyl" TRF) were repeated using a p-L-glutamyl residue, and the minimum-energy results are given below ( Table 1). The dihedral angles for all conformations are essentially the same except that the sign of {l is reversed. It should be noted that the N8 conformer of structure D is now only 0.1 kcal/mol higher in energy than conformer NE of structure A. The similarity of the "p-D-glutamyl" and "p-L-glutamyl" TRF conformations suggests that the former should be active as a thyrotropin releasing factor.

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Section: Geometry Of Trfmentioning

confidence: 99%

Conformational Analysis of Thyrotropin Releasing Factor

Burgess

Momany

Scheraga

1973

Proc. Natl. Acad. Sci. U.S.A.

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“…The model was then optimized using energy minimization and molecular simulation calculations. The accuracy of the model was checked using Ramachandran plot (27) and by profile analyses (28). The binding sites involved in direct interaction between TRANCE and OPG were analyzed and used as the initial template for peptide design, as shown in Table I.…”

Section: Materials and Cellmentioning

confidence: 99%

Disabling of Receptor Activator of Nuclear Factor-κB (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo

Cheng

Kinosaki

Miki

et al. 2004

Journal of Biological Chemistry

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The tumor necrosis factor family ligand, tumor necrosis factor-related activation-induced cytokine (TRANCE), and its receptors, receptor activator of nuclear factor-B (RANK) and osteoprotegerin (OPG), are known to be regulators of development and activation of osteoclasts in bone remodeling. Sustained osteoclast activation that occurs through TRANCE-RANK causes osteopenic disorders such as osteoporosis and contributes to osteolytic metastases. Here, we report a rationally designed small molecule mimic of osteoprotegerin to inhibit osteoclast formation in vitro and limit bone loss in an animal model of osteoporosis. One of the mimetics, OP3-4, significantly inhibited osteoclast formation in vitro (IC 50 ‫؍‬ 10 M) and effectively inhibited total bone loss in ovariectomized mice at a dosage of 2 mg/kg/day. Unlike soluble OPG receptors, which preclude TRANCE binding to RANK, OP3-4 shows the ability to modulate RANK-TRANCE signaling pathways and alters the biological functions of the RANK-TRANCE receptor complex by facilitating a defective receptor complex. These features suggest that OPG-derived small molecules can be used as a probe to understand complex biological functions of RANK-TRANCE-OPG receptors and also can be used as a platform to develop more useful therapeutic agents for inflammation and bone disease. TRANCE,1 a TNF family member, also known as OPGL, RANKL, ODF, and OCIF, plays a key role in the development of osteoclasts and in modulating their bone resorbing activity (1-4). Increased osteoclast activity has been reported in many osteopenic disorders, including postmenopausal osteoporosis, Paget's disease, bone metastases, and rheumatoid arthritis (5-7). TRANCE interacts with two receptors: a secreted decoy receptor osteoprotegerin, OPG (8), and a transmembrane receptor, RANK (9 -11). The interaction between TRANCE and RANK is essential for osteoclastogenesis because RANK is activated by TRANCE and then associates with TNF receptorassociated family members to trigger downstream signaling (11) events. OPG, on the other hand, plays an opposite role by preventing TRANCE from binding and activating RANK and thus is considered a "decoy" receptor. In this way, the interaction between TRANCE and OPG or TRANCE and RANK represents a complex network required for normal bone development, and any imbalance in the system potentially leads to bone disorders. Thus it is well recognized that this receptor complex network is an interesting drug development target for the treatment of bone disorders such as osteoporosis (12), and there is considerable interest in developing ways to modulate RANK functions which may prove beneficial for bone-related pathologies.To date there is no three-dimensional structural information available for the RANK receptor complex. However, it is believed that the complex should resemble that of the TNF receptor as a member of TNF superfamily. The TNF-␤⅐TNFR1 co-crystal structure has been solved, thus facilitating rational drug design based on the receptor-ligand interaction sites coupled wi...

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“…The greater difference arises from the absence of a steric clash in the trans conformation. Although conformational constraints can force a nonprolyl peptide bond to be cis (Ramachandran & Venkatachalam, 1968), only 0.05% of nonprolyl peptide bonds are cis in known protein structures (Stewart et al, 1990). Most of these bonds are near the active sites of enzymes (Herzberg & Moult, 1991).…”

mentioning

confidence: 99%

“…Although glycine has much accessible conformational space, formation of a cis glycyl peptide bond is still destabilizing (Ramachandran & Venkatachalam, 1968). Nonetheless, the inherent conformational flexibility of glycine apparently allows the formation of a type 11 turn with all trans peptide bonds within the restricted 91-94 turn of RNase A.…”

mentioning

confidence: 99%

Structure and stability of the P93G variant of ribonuclease A

et al. 1998

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Abstract:The peptide bonds preceding Pro 93 and Pro I14 of bovine pancreatic ribonuclease A (RNase A) are in the cis conformation. The trans-to-cis isomerization of these bonds had been indicted as the slow step during protein folding. Here, site-directed mutagenesis was used to replace Pro 93 or Pro 114 with a glycine residue, and the crystalline structure of the P93G variant was determined by X-ray diffraction analysis to a resolution of 1.7 w.This structure is essentially identical to that of the wild-type protein, except for the 9 1-94 p-turn containing the substitution. In the wild-type protein, the p-turn is of type Vla. In the P93G variant, this turn is of type I1 with the peptide bond preceding Gly 93 being trans. The thermal stabilities of the P93G and P114G variants were assessed by differential scanning calorimetry and thermal denaturation experiments monitored by ultraviolet spectroscopy. The value of AAGm, which reports on the stability lost in the variants, is 1 S-fold greater for the PI 14G variant than for the P93G variant. The greater stability of the P93G variant is likely due to the relatively facile accommodation of residues 91-94 in a type I1 turn, which has a preference for a glycine residue in its i + 2 position.

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Stereochemical criteria for polypeptides and proteins. IV. Standard dimensions for the cis‐peptide unit and conformation of cis‐polypeptides

Cited by 53 publications

References 6 publications

Conformational Analysis of Thyrotropin Releasing Factor

Conformational Analysis of Thyrotropin Releasing Factor

Disabling of Receptor Activator of Nuclear Factor-κB (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo

Structure and stability of the P93G variant of ribonuclease A

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