title: Crystallography and protein-protein interactions: biological interfaces and crystal contacts.
abstract: Crystallography is commonly used for studying the structures of protein-protein complexes. However, a crystal structure does not define a unique protein-protein interface, and distinguishing a 'biological interface' from 'crystal contacts' is often not straightforward. A number of computational approaches exist for distinguishing them, but their error rate is high, emphasizing the need to obtain further data on the biological interface using complementary structural and functional approaches. In addition to reviewing the computational and experimental approaches for addressing this problem, we highlight two relevant examples. The first example from our laboratory involves the structure of acyl-CoA thioesterase 7, where each domain of this two-domain protein was crystallized separately, but both yielded a non-functional assembly. The structure of the full-length protein was uncovered using a combination of complementary approaches including chemical cross-linking, analytical ultracentrifugation and mutagenesis. The second example involves the platelet glycoprotein Ibalpha-thrombin complex. Two groups reported the crystal structures of this complex, but all the interacting interfaces differed between the two structures. Our computational analysis did not fully resolve the reasons for the discrepancies, but provided interesting insights into the system. This review highlights the need to complement crystallographic studies with complementary experimental and computational approaches.
authors.affiliation: School of Molecular and Microbial Sciences, The University of Queensland, Brisbane, QLD, Australia. b.kobe@uq.edu.au
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
authors.forename: Gregor
authors.initials: G
authors.lastname: Guncar
authors.forename: Rebecca
authors.initials: R
authors.lastname: Buchholz
authors.forename: Thomas
authors.initials: T
authors.lastname: Huber
authors.forename: Bohumil
authors.initials: B
authors.lastname: Maco
authors.forename: Nathan
authors.initials: N
authors.lastname: Cowieson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Martin
authors.forename: Mary
authors.initials: M
authors.lastname: Marfori
authors.forename: Jade K
authors.initials: JK
authors.lastname: Forwood
mesh_terms: D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry; D008958:Models, Molecular; D010170:Palmitoyl-CoA Hydrolase / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013917:Thrombin / Q000737:chemistry
chemical_list: D006023:Glycoproteins; D011506:Proteins; D010170:Palmitoyl-CoA Hydrolase; D013917:Thrombin