PubMed · 9276248
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P Güntert. 1997. Calculating protein structures from NMR data.. https://doi.org/10.1385/0-89603-309-0%3A157
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BACKGROUND: The technique of deep hypothermic circulatory arrest (DHCA) for cardiothoracic surgery is associated with increased risk for perioperative blood loss and renal dysfunction. Although aprotinin, a serine protease inhibitor, reduces blood loss in patients undergoing cardiopulmonary bypass, its use has been limited in the setting of DHCA because of concerns regarding aprotinin-induced renal dysfunction. Therefore, we assessed the affect of aprotinin on both blood transfusion requirements and renal function in patients undergoing cardiovascular surgery and DHCA. METHODS AND RESULTS: We reviewed the records of 853 patients who underwent aortic or thoracoabdominal surgery at Stanford University Medical Center between January 1992 and March 2000. Two hundred three of these patients were treated with DHCA, and 90% (183) survived for more than 24 hours. Preoperative patient characteristics and intraoperative and postoperative clinical and surgical variables were recorded, and creatinine clearance (CRCl) was calculated for the preoperative and postoperative periods; renal dysfunction was prospectively defined as a 25% reduction in CRCl. The association between perioperative variables, including aprotinin use, and renal dysfunction was assessed by ANOVA techniques. Total urine output was 1294+/-1024 mL and 3492+/-1613 mL during and after surgery, respectively. CRCl decreased significantly after DHCA from 86+/-8 mL/min (before surgery) to 67+/-4 mL/min (in the intensive care unit) (P<0.01). Thirty-eight percent of patients (70 of 183) had postoperative renal dysfunction. Multivariate regression analyses identified 5 factors independently associated with a >25% reduction in CRCl: requirement for >/=5 U of packed red blood cells(P=0.0002; OR=2.1), </=800 mL of urine collected in the operating room (P=0.0011; OR=1.9), nonuse of dopamine (P=0.0430; OR=1.6), hematocrit </=21 mg% (P=0.0343; OR=1.5), and </=2100 mL of urine during the first 24 hours in the intensive care unit (P=0.0039; OR=2.0). Aprotinin did not increase the likelihood of postoperative renal dysfunction (P=0.951), nor did it significantly reduce packed red blood cell transfusion requirements in either primary (n=107) (P=0.456) or reoperative cardiovascular (n=76) (P=0.176) procedures. During the operative period, the aprotinin group received a greater number of units of platelets (10.0 versus 6.6 U, P<0.012), fresh frozen plasma (4.8 versus 3.1 U, P<0.03), and cryoprecipitate (9.9 versus 5.4 U, P<0.002) than patients not prescribed aprotinin. Similarly, patients given aprotinin received more cryoprecipitate in the intensive care unit (7.3 versus 3.0 U, P<0.024). CONCLUSIONS: These data suggest that the administration of aprotinin to patients treated with DHCA does not increase the risk of renal dysfunction. However, aprotinin may not ameliorate the problem of perioperative blood loss in DHCA. Patients with greater requirements for packed red blood cell transfusions or reduced urine production are more likely to have postoperative renal dysfunction. Dopamine may provide renal protection in the setting of DHCA.
Characterization of protein surface accessibility represents a new frontier of structural biology. A surface accessibility investigation for two structurally well-defined proteins, tendamistat and bovine pancreatic trypsin inhibitor, is performed here by a combined analysis of water-protein Overhauser effects and paramagnetic perturbation profiles induced by the soluble spin-label 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl on NMR spectra. This approach seems to be reliable not only for distinguishing between buried and exposed residues but also for finding molecular locations where a network of more ordered waters covers the protein surface. From the presented set of data, an overall picture of the surface accessibility of the two proteins can be inferred. Detailed knowledge of protein accessibility can form the basis for successful design of mutants with increased activity and/or greater specificity.
The crystal structure of a mutant of bovine pancreatic trypsin inhibitor has been refined to 0.86 A resolution using low-temperature synchrotron data. The variant contains three mutations in the binding loop (Thr11Ala, Pro13Ala, Lys15Arg) and an unrelated Met52Leu substitution. Refinement with anisotropic displacement parameters and with removal of main-chain stereochemical restraints converged with R = 0.1035. The use of full-matrix refinement provided an estimate of the variances in the derived parameters. Some stereochemical parameters, such as the planarity of the peptide group and the value of the N-C(alpha)-C angle, show a wide spread, suggesting that the standard values used as restraints in protein structure refinements may not always be entirely appropriate. Comparison with the recently determined room-temperature structure of the same mutant at 1.42 A resolution confirms the previous observations and provides new details, such as a double conformation of the main chain at Leu29 and at Gly56-Gly57, a high proportion (over 20%) of residues in double conformations, correlation of disorder through lattice contacts and the positions of H atoms, including those in water molecules, and their involvement in C-H...O and N-H...pi hydrogen bonds.